Martha L. Slattery

Fast-food consumption has increased greatly in the USA during the past three decades. However, the effect of fast food on risk of obesity and type 2 diabetes has received little attention. We aimed to investigate the association between reported fast-food habits and changes in bodyweight and insulin resistance over a 15-year period in the USA.Participants for the CARDIA study included 3031 young (age 18-30 years in 1985-86) black and white adults who were followed up with repeated dietary assessment. We used multiple linear regression models to investigate the association of frequency of fast-food restaurant visits (fast-food frequency) at baseline and follow-up with 15-year changes in bodyweight and the homoeostasis model (HOMA) for insulin resistance.Fast-food frequency was lowest for white women (about 1.3 times per week) compared with the other ethnic-sex groups (about twice a week). After adjustment for lifestyle factors, baseline fast-food frequency was directly associated with changes in bodyweight in both black (p=0.0050) and white people (p=0.0013). Change in fast-food frequency over 15 years was directly associated with changes in bodyweight in white individuals (p<0.0001), with a weaker association recorded in black people (p=0.1004). Changes were also directly associated with insulin resistance in both ethnic groups (p=0.0015 in black people, p<0.0001 in white people). By comparison with the average 15-year weight gain in participants with infrequent (less than once a week) fast-food restaurant use at baseline and follow-up (n=203), those with frequent (more than twice a week) visits to fast-food restaurants at baseline and follow-up (n=87) gained an extra 4.5 kg of bodyweight (p=0.0054) and had a two-fold greater increase in insulin resistance (p=0.0083).Fast-food consumption has strong positive associations with weight gain and insulin resistance, suggesting that fast food increases the risk of obesity and type 2 diabetes.

Components of the insulin resistance syndrome (IRS), including obesity, glucose intolerance, hypertension, and dyslipidemia, are major risk factors for type 2 diabetes and heart disease. Although diet has been postulated to influence IRS, the independent effects of dairy consumption on development of this syndrome have not been investigated.To examine associations between dairy intake and incidence of IRS, adjusting for confounding lifestyle and dietary factors.The Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based prospective study.General community sample from 4 US metropolitan areas of 3157 black and white adults aged 18 to 30 years who were followed up from 1985-1986 to 1995-1996.Ten-year cumulative incidence of IRS and its association with dairy consumption, measured by diet history interview.Dairy consumption was inversely associated with the incidence of all IRS components among individuals who were overweight (body mass index > or =25 kg/m(2)) at baseline but not among leaner individuals (body mass index < 25 kg/m(2)). The adjusted odds of developing IRS (2 or more components) were 72% lower (odds ratio, 0.28; 95% confidence interval, 0.14-0.58) among overweight individuals in the highest (> or =35 times per week, 24/102 individuals) compared with the lowest (<10 times per week, 85/190 individuals) category of dairy consumption. Each daily occasion of dairy consumption was associated with a 21% lower odds of IRS (odds ratio, 0.79; 95% confidence interval, 0.70-0.88). These associations were similar for blacks and whites and for men and women. Other dietary factors, including macronutrients and micronutrients, did not explain the association between dairy intake and IRS.Dietary patterns characterized by increased dairy consumption have a strong inverse association with IRS among overweight adults and may reduce risk of type 2 diabetes and cardiovascular disease.

We tested the hypothesis that dietary intervention can inhibit the development of recurrent colorectal adenomas, which are precursors of most large-bowel cancers.We randomly assigned 2079 men and women who were 35 years of age or older and who had had one or more histologically confirmed colorectal adenomas removed within six months before randomization to one of two groups: an intervention group given intensive counseling and assigned to follow a diet that was low in fat (20 percent of total calories) and high in fiber (18 g of dietary fiber per 1000 kcal) and fruits and vegetables (3.5 servings per 1000 kcal), and a control group given a standard brochure on healthy eating and assigned to follow their usual diet. Subjects entered the study after undergoing complete colonoscopy and removal of adenomatous polyps; they remained in the study for approximately four years, undergoing colonoscopy one and four years after randomization.A total of 1905 of the randomized subjects (91.6 percent) completed the study. Of the 958 subjects in the intervention group and the 947 in the control group who completed the study, 39.7 percent and 39.5 percent, respectively, had at least one recurrent adenoma; the unadjusted risk ratio was 1.00 (95 percent confidence interval, 0.90 to 1.12). Among subjects with recurrent adenomas, the mean (+/-SE) number of such lesions was 1.85+/-0.08 in the intervention group and 1.84+/-0.07 in the control group. The rate of recurrence of large adenomas (with a maximal diameter of at least 1 cm) and advanced adenomas (defined as lesions that had a maximal diameter of at least 1 cm or at least 25 percent villous elements or evidence of high-grade dysplasia, including carcinoma) did not differ significantly between the two groups.Adopting a diet that is low in fat and high in fiber, fruits, and vegetables does not influence the risk of recurrence of colorectal adenomas.

Journal Article Colon Cancer: A Review of the Epidemiology Get access John D. Potter, John D. Potter 1Division of Epidemiology, School of Public Health, University of MinnesotaMinneapolis, MN Dr. John D. Potter, Division of Epidemiology, School of Public Health, University of Minnesota, 1300 South Second Street, Minneapolis, MN 55454 Search for other works by this author on: Oxford Academic PubMed Google Scholar Martha L. Slattery, Martha L. Slattery 2Department of Family and Preventive Medicine, School of Medicine, University of UtahSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar Roberd M. Bostick, Roberd M. Bostick 1Division of Epidemiology, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar Susan M. Gapstur Susan M. Gapstur 1Division of Epidemiology, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar Epidemiologic Reviews, Volume 15, Issue 2, 1993, Pages 499–545, https://doi.org/10.1093/oxfordjournals.epirev.a036132 Published: 01 July 1993 Article history Received: 21 January 1993 Published: 01 July 1993 Revision received: 17 August 1993

The BRAF V600E mutation has been associated with microsatellite instability and the CpG island methylator phenotype (CIMP) in colon cancer. We evaluated a large population-based sample of individuals with colon cancer to determine its relationship to survival and other clinicopathologic variables. The V600E BRAF mutation was seen in 5% (40 of 803) of microsatellite-stable tumors and 51.8% (43 of 83) of microsatellite-unstable tumors. In microsatellite-stable tumors, this mutation was related to poor survival, CIMP high, advanced American Joint Committee on Cancer (AJCC) stage, and family history of colorectal cancer [odds ratio, 4.23; 95% confidence interval (95% CI), 1.65-10.84]. The poor survival was observed in a univariate analysis of 5-year survival (16.7% versus 60.0%; P < 0.01); in an analysis adjusted for age, stage, and tumor site [hazard rate ratio (HRR), 2.97; 95% CI, 2.05-4.32]; in stage-specific, age-adjusted analyses for AJCC stages 2 to 4 (HRR, 4.88, 3.60, and 2.04, respectively); and in Kaplan-Meier survival estimates for AJCC stages 2 to 4 (P < 0.01 for all three stages). Microsatellite-unstable tumors were associated with an excellent 5-year survival whether the V600E mutation was present or absent (76.2% and 75.0%, respectively). We conclude that the BRAF V600E mutation in microsatellite-stable colon cancer is associated with a significantly poorer survival in stages 2 to 4 colon cancer but has no effect on the excellent prognosis of microsatellite-unstable tumors.

Dietary composition may affect insulin secretion, and high insulin levels, in turn, may increase the risk for cardiovascular disease (CVD).To examine the role of fiber consumption and its association with insulin levels, weight gain, and other CVD risk factors compared with other major dietary components.The Coronary Artery Risk Development in Young Adults (CARDIA) Study, a multicenter population-based cohort study of the change in CVD risk factors over 10 years (1985-1986 to 1995-1996) in Birmingham, Ala; Chicago, III; Minneapolis, Minn; and Oakland, Calif.A total of 2909 healthy black and white adults, 18 to 30 years of age at enrollment.Body weight, insulin levels, and other CVD risk factors at year 10, adjusted for baseline values.After adjustment for potential confounding factors, dietary fiber showed linear associations from lowest to highest quintiles of intake with the following: body weight (whites: 174.8-166.7 lb [78.3-75.0 kg], P<.001; blacks: 185.6-177.6 lb [83.5-79.9 kg], P = .001), waist-to-hip ratio (whites: 0.813-0.801, P = .004; blacks: 0.809-0.799, P = .05), fasting insulin adjusted for body mass index (whites: 77.8-72.2 pmol/L [11.2-10.4 microU/mL], P = .007; blacks: 92.4-82.6 pmol/L [13.3-11.9 microU/mL], P = .01) and 2-hour postglucose insulin adjusted for body mass index (whites: 261.1-234.7 pmol/L [37.6-33.8 microU/mL], P = .03; blacks: 370.2-259.7 pmol/L [53.3-37.4 microU/mL], P<.001). Fiber was also associated with blood pressure and levels of triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and fibrinogen; these associations were substantially attenuated by adjustment for fasting insulin level. In comparison with fiber, intake of fat, carbohydrate, and protein had inconsistent or weak associations with all CVD risk factors.Fiber consumption predicted insulin levels, weight gain, and other CVD risk factors more strongly than did total or saturated fat consumption. High-fiber diets may protect against obesity and CVD by lowering insulin levels.

Colon cancer has been associated with several nutrients and foods. The authors used data from a population-based study conducted in Northern California, Utah, and Minnesota to examine associations between dietary eating patterns and risk of developing colon cancer. Through factor analysis, detailed dietary intake data obtained from 1,993 cases (diagnosed in 1991-1994) and 2,410 controls were grouped into factors that were evaluated for relations with lifestyle characteristics and colon cancer risk. Several dietary patterns emerged. The dietary patterns with the most variation were labeled "Western," "prudent," "high fat/sugar dairy," "substituters," and "drinkers." The "Western" dietary pattern was associated with a higher body mass index and a greater intake of total energy and dietary cholesterol. The "prudent" pattern was associated with higher levels of vigorous leisure time physical activity, smaller body size, and higher intakes of dietary fiber and folate. Persons who had high scores on the "drinker" pattern were also more likely to smoke cigarettes. The "Western" dietary pattern was associated with an increased risk of colon cancer in both men and women. The association was strongest among people diagnosed prior to age 67 years (for men, odds ratio (OR)=1.96, 95% confidence interval (CI) 1.22-3.15; for women, OR=2.02, 95% CI 1.21-3.36) and among men with distal tumors (OR=2.25, 95% CI 1.47-3.46). The "prudent" diet was protective, with the strongest associations being observed among people diagnosed prior to age 67 years (men: OR=0.63, 95% CI 0.43-0.92; women: OR=0.58, 95% CI 0.38-0.87); associations with this dietary pattern were also strong among persons with proximal tumors (men: OR=0.55, 95% CI 0.38-0.80; women: OR=0.64, 95% CI 0.45-0.92). Although "substituters" (people who substituted low fat dairy products for high fat dairy products, margarine for butter, poultry for red meat, and whole grains for refined grains) were at reduced risk of colon cancer, the reduction in risk was not statistically significant. These data support the hypothesis that overall dietary intake pattern is associated with colon cancer, and that the dietary pattern associated with the greatest increase in risk is the one which typifies a Western-style diet.

Background & Aims: The concept of a CpG island methylator phenotype (CIMP), especially in microsatellite stable colon cancer, is not accepted universally. We therefore evaluated a large population-based sample of individuals with colon cancer and used univariate and multivariate analyses of CIMP with clinicopathologic variables and tumor mutations to determine the biologic relevance of this phenotype. Methods: A total of 864 tumors from individuals with colon cancer from Utah and Northern California were evaluated by methylation-specific polymerase chain reaction of CpG islands in hMLH1, methylated in tumors (MINT) 1, MINT 2, MINT 31, and CDKN2A (p16). CIMP high was defined as methylation at 2 or more of these loci. The BRAF V600E mutation was determined by sequencing. Microsatellite instability had been determined previously. Results: In a multivariate analysis of microsatellite stable tumors, CIMP high was related significantly to the V600E BRAF mutation (odds ratio, 39.52; 95% confidence interval, 11.44–136.56), KRAS2 mutations (odds ratio, 2.22; 95% confidence interval, 1.48–3.34), older age (P trend = .03), and increased stage (P trend = .03), and these tumors were less likely to be located in the distal colon (odds ratio, .42; 95% confidence interval, .27–.65). CIMP-high unstable tumors also were more likely to have the V600E BRAF mutation, be located proximally, and occur in older individuals (in univariate analyses). However, CIMP-high unstable tumors were significantly more likely than their stable counterparts to be KRAS2 wild type, TP53 wild type, poorly differentiated, proximally located, occur at lower stages, and have the BRAF V600E mutation (64.1% vs 17.6%). Conclusions: The evaluation of a large, population-based sample strongly supports the biologic relevance of CIMP in colon cancer. However, the presence or absence of microsatellite instability has a major effect on the expression of this phenotype. Background & Aims: The concept of a CpG island methylator phenotype (CIMP), especially in microsatellite stable colon cancer, is not accepted universally. We therefore evaluated a large population-based sample of individuals with colon cancer and used univariate and multivariate analyses of CIMP with clinicopathologic variables and tumor mutations to determine the biologic relevance of this phenotype. Methods: A total of 864 tumors from individuals with colon cancer from Utah and Northern California were evaluated by methylation-specific polymerase chain reaction of CpG islands in hMLH1, methylated in tumors (MINT) 1, MINT 2, MINT 31, and CDKN2A (p16). CIMP high was defined as methylation at 2 or more of these loci. The BRAF V600E mutation was determined by sequencing. Microsatellite instability had been determined previously. Results: In a multivariate analysis of microsatellite stable tumors, CIMP high was related significantly to the V600E BRAF mutation (odds ratio, 39.52; 95% confidence interval, 11.44–136.56), KRAS2 mutations (odds ratio, 2.22; 95% confidence interval, 1.48–3.34), older age (P trend = .03), and increased stage (P trend = .03), and these tumors were less likely to be located in the distal colon (odds ratio, .42; 95% confidence interval, .27–.65). CIMP-high unstable tumors also were more likely to have the V600E BRAF mutation, be located proximally, and occur in older individuals (in univariate analyses). However, CIMP-high unstable tumors were significantly more likely than their stable counterparts to be KRAS2 wild type, TP53 wild type, poorly differentiated, proximally located, occur at lower stages, and have the BRAF V600E mutation (64.1% vs 17.6%). Conclusions: The evaluation of a large, population-based sample strongly supports the biologic relevance of CIMP in colon cancer. However, the presence or absence of microsatellite instability has a major effect on the expression of this phenotype. The concept of a CpG island methylator phenotype (CIMP) has had a complicated and somewhat controversial history. CIMP refers to the notion that a subset of tumors has widespread methylation of CpG islands that leads to epigenetic inactivation of tumor suppressor genes by promoter methylation. The original studies of 88 individuals with colorectal cancer reported CIMP in approximately 50% of colon cancers and noted significant relationships with proximal location, mutant KRAS2, and wild type TP53, relationships that were reported to be independent of microsatellite instability.1Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Crossref PubMed Scopus (2157) Google Scholar, 2Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Crossref PubMed Scopus (407) Google Scholar Two subsequent studies of relatively larger numbers of unselected colorectal cancer patients reported less frequent widespread methylation of CpG islands, especially if microsatellite unstable tumors were excluded, ranging from 12% to 25%.3Hawkins N. Norrie M. Cheong K. et al.CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar, 4van Rijnsoever M. Grieu F. Elsaleh H. Joseph D. Iacopetta B. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands.Gut. 2002; 51: 797-802Crossref PubMed Scopus (217) Google Scholar Hawkins et al,3Hawkins N. Norrie M. Cheong K. et al.CpG island methylation in sporadic colorectal cancers and its relationship to microsatellite instability.Gastroenterology. 2002; 122: 1376-1387Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar in a study of 396 individuals, reported relationships between CIMP and proximal location, female sex, older age, high tumor grade, mucinous histology, wild-type TP53, microsatellite instability, and mutant KRAS2. However, if microsatellite unstable tumors were excluded, significant relationships were seen only with older age, proximal location, mucinous histology, and mutant KRAS2. Rijnsoever et al,4van Rijnsoever M. Grieu F. Elsaleh H. Joseph D. Iacopetta B. Characterisation of colorectal cancers showing hypermethylation at multiple CpG islands.Gut. 2002; 51: 797-802Crossref PubMed Scopus (217) Google Scholar in a study of 275 individuals, reported relationships between CIMP and poor differentiation, wild-type TP53, proximal location, and higher stage, with or without inclusion of microsatellite unstable tumors. Recent studies also have identified an excess of the BRAF V600E mutation in CIMP-high stable and unstable tumors.5Kambara T. Simms L.A. Whitehall V.L. et al.BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum.Gut. 2004; 53: 1137-1144Crossref PubMed Scopus (624) Google Scholar, 6Nagasaka T. Sasamoto H. Notohara K. et al.Colorectal cancer with mutation in BRAF, KRAS, and wild-type with respect to both oncogenes showing different patterns of DNA methylation.J Clin Oncol. 2004; 22: 4584-4594Crossref PubMed Scopus (197) Google Scholar Microsatellite instability by itself has been associated with an inverse relationship with KRAS2 and TP53 mutations, a better prognosis than stable tumors, and proximal tumor location.7Samowitz W.S. Curtin K. Ma K.N. et al.Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar, 8Samowitz W.S. Holden J.A. Curtin K. et al.Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer.Am J Pathol. 2001; 158: 1517-1524Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar The majority of sporadic microsatellite unstable tumors also are methylated heavily,1Toyota M. Ahuja N. Ohe-Toyota M. Herman J.G. Baylin S.B. Issa J.P. CpG island methylator phenotype in colorectal cancer.Proc Natl Acad Sci U S A. 1999; 96: 8681-8686Crossref PubMed Scopus (2157) Google Scholar, 2Toyota M. Ohe-Toyota M. Ahuja N. Issa J.P. Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype.Proc Natl Acad Sci U S A. 2000; 97: 710-715Crossref PubMed Scopus (407) Google Scholar and it therefore may be important to consider the CIMP status of tumors with and without microsatellite instability separately to ascertain the true contribution of CIMP to these various relationships. The relationship of CIMP to family history also is controversial, with 1 study reporting a relationship between CIMP and family history of cancer yet another study showed no such relationship.9Frazier M.L. Xi L. Zong J. et al.Association of the CpG island methylator phenotype with family history of cancer in patients with colorectal cancer.Cancer Res. 2003; 63: 4805-4808PubMed Google Scholar, 10Ward R.L. Williams R. Law M. Hawkins N.J. The CpG island methylator phenotype is not associated with a personal or family history of cancer.Cancer Res. 2004; 64: 7618-7621Crossref PubMed Scopus (25) Google Scholar Finally, the entire notion of CIMP recently has been challenged, with the assertion that the division of CIMP-negative and CIMP-positive tumors is arbitrary and that without inclusion of microsatellite unstable cancers most of the reported relationships with CIMP, other than age and proximal location, disappear.11Yamashita K. Dai T. Dai Y. Yamamoto F. Perucho M. Genetics supersedes epigenetics in colon cancer phenotype.Cancer Cell. 2003; 4: 121-131Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar It should be noted that although some of the previous studies of CIMP were unselected, none were population based. Also, none of the previous studies performed multivariate analyses of CIMP and its relationships or had sufficient power to compare adequately CIMP-high stable with CIMP-high unstable carcinomas. In this study we have determined the significance of CIMP with and without microsatellite instability. We also compare CIMP-high stable and unstable carcinomas and perform multivariate analyses of CIMP and its clinicopathologic relationships to determine whether relationships independent of age and/or proximal location exist in stable tumors. Study participants were white, black, or Hispanic and were from either the Kaiser Permanente Medical Care Program of Northern California or an 8-county area in Utah (Davis, Salt Lake, Utah, Weber, Wasatch, Tooele, Morgan, and Summit counties). Eligibility criteria for inclusion in the study included diagnosis with first primary incident colon cancer (International Classification of Diseases, 9th revision, 2nd edition codes 18.0 and 18.2–18.9) between October 1, 1991, and September 30, 1994, age between 30 and 79 years at the time of diagnosis, and mentally competent to participate in the study. Patients with cancer of the rectosigmoid junction or rectum (defined as the first 15 cm from the anal opening) or with known familial adenomatous polyposis, ulcerative colitis, or Crohn’s disease were not eligible. All cases were adenocarcinomas or carcinomas. This study population is part of a previously described sample.12Slattery M.L. Potter J. Caan B. et al.Energy balance and colon cancer—beyond physical activity.Cancer Res. 1997; 57: 75-80PubMed Google Scholar Tumor blocks and amplifiable DNA originally were available for 1530 individuals; this represents 84% of all individuals diagnosed with colon cancer, making this a truly population-based sample. This sample has been used for previous population-based studies on KRAS2, TP53, and microsatellite instability.7Samowitz W.S. Curtin K. Ma K.N. et al.Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar, 13Samowitz W.S. Curtin K. Schaffer D. Robertson M. Leppert M. Slattery M.L. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival a population-based study.Cancer Epidemiol Biomarkers Prev. 2000; 9: 1193-1197PubMed Google Scholar, 14Samowitz W.S. Curtin K. Ma K.N. et al.Prognostic significance of p53 mutations in colon cancer at the population level.Int J Cancer. 2002; 99: 597-602Crossref PubMed Scopus (128) Google Scholar Sufficient DNA for determination of CIMP (which requires a fairly large aliquot of DNA) was available for tumors from 864 individuals. This group did not differ from those for whom CIMP was not determined with respect to age, American Joint Committee on Cancer (AJCC) stage, histologic differentiation, tumor site, prognosis, or family history of colorectal cancer (data available on request). Information on age at time of diagnosis, sex, tumor site, and tumor stage was available from the Northern California Tumor Registry, the Sacramento Tumor Registry, and the Utah Cancer Registry. These registries are members of the Surveillance, Epidemiology, and End Results program. Tumors occurring in the cecum through the transverse colon were defined as proximal; tumors in the splenic flexure, descending, and sigmoid colon were defined as distal. Tumors were staged according to AJCC15American Joint Committee on CancerAJCC cancer staging manual. 5th ed. Lippincott-Raven, Philadelphia1997Google Scholar criteria and the histologic grade and presence or absence of mucinous histology was determined by reviewing pathology reports. Because we did not have access to complete medical records, AJCC stage IV tumors were identified by using Surveillance, Epidemiology, and End Results program summary stage codes to determine whether distant metastases were present. All aspects of this study were approved by the University of Utah and Kaiser Permanente Medical Care Program institutional review boards. Sodium bisulfate modification was performed on DNA extracted from tumors microdissected for previous studies.7Samowitz W.S. Curtin K. Ma K.N. et al.Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar Methylation-specific polymerase chain reaction then was performed as described previously for the following CpG islands: methylated in tumors (MINT) 1, MINT 2, MINT 31, CDKN2A(p16), and hMLH1.16Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar This panel was being used at the time our study began by the group who originally described CIMP and its importance in colorectal cancer, and their criterion for CIMP high was methylation of 2 or more of these CpG islands.16Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar Methylation was defined as a recognizable band on an agarose gel by using the methylation-specific primers. CIMP low was defined as less than 2 of 5 markers methylated. The primers used for hMLH1 methylation as part of the CIMP panel are located approximately 170 and 270 base pairs 5′ of the start codon. We also determined hMLH1 methylation by using a different set of primers located approximately 650–800 base pairs 5′ to the start codon,17Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Crossref PubMed Scopus (5250) Google Scholar but this result was not used for the determination of CIMP high and low. The BRAF V600E mutation was detected by amplifying exon 15 of BRAF by using the forward primer 5′-TCA TAA TGC TTG CTC TGA TAG GA-3′ and the reverse primer 5′-CTT TCT AGT AAC TCA GCA GC-3′. Amplifications were performed using AmpliTaq Gold (Applied Biosystems, Foster City, CA) and a polymerase chain reaction profile consisting of a 9-minute initial denaturation at 95°C, then 35 cycles of 20 seconds at 95°C, 20 seconds at 60°C, and 30 seconds at 72°C, with a 5-minute final extension at 72°C. Mutations were verified by sequencing in both directions. Codons 12 and 13 KRAS2 mutations, TP53 mutations in exons 5–8, and microsatellite instability were determined in previous studies.7Samowitz W.S. Curtin K. Ma K.N. et al.Microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.Cancer Epidemiol Biomarkers Prev. 2001; 10: 917-923PubMed Google Scholar, 13Samowitz W.S. Curtin K. Schaffer D. Robertson M. Leppert M. Slattery M.L. Relationship of Ki-ras mutations in colon cancers to tumor location, stage, and survival a population-based study.Cancer Epidemiol Biomarkers Prev. 2000; 9: 1193-1197PubMed Google Scholar, 14Samowitz W.S. Curtin K. Ma K.N. et al.Prognostic significance of p53 mutations in colon cancer at the population level.Int J Cancer. 2002; 99: 597-602Crossref PubMed Scopus (128) Google Scholar These studies preceded the development of the Bethesda consensus panel; the microsatellite instability markers used were BAT-26 (a mononucleotide repeat that by itself is a very good measure of generalized instability18Hoang J.-M. Cottu P.H. Thuille B. Salmon R.J. Thomas G. Hamelin R. BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines.Cancer Res. 1997; 57: 300-303PubMed Google Scholar), transforming growth factor β receptor type II (TGF-β RII; a coding mononucleotide repeat that is unstable in most colorectal cancers with microsatellite instability), and a panel of 10 tetranucleotide repeats that show a high correlation with the Bethesda consensus panel and BAT-26.8Samowitz W.S. Holden J.A. Curtin K. et al.Inverse relationship between microsatellite instability and K-ras and p53 gene alterations in colon cancer.Am J Pathol. 2001; 158: 1517-1524Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar A hierarchic approach then was used for microsatellite instability determination. A total of 784 tumors were classified (either stable or unstable) for BAT-26. Fifty-three tumors (which did not show results for BAT-26) were classified by using TGFβRII and 3 tumors (which showed no results for either BAT-26 or TGFβRII) were classified by using the panel of 10 tetranucleotide repeats; in that case, if 30% or more of the 10 tetranucleotide repeats were unstable, the tumor was classified as unstable, and if less than 30% were unstable the tumor was classified as stable. Microsatellite instability data were available on 840 of the 864 tumors evaluable by CIMP. Differences in the proportion of microsatellite stable and unstable tumors in those tumors classified as CIMP high or with hMLH1 methylation (using the 2 sets of primers described earlier under CIMP16Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 17Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Crossref PubMed Scopus (5250) Google Scholar) were evaluated by using χ2 statistics. Univariate relationships between CIMP and age, tumor site, AJCC stage, sex, differentiation, a positive histologic classification of mucinous, mucin-producing, or signet ring, KRAS2 mutations, TP53 mutations, and the BRAF V600E mutation were evaluated using logistic regression to calculate crude odds ratios. Multivariate logistic regression was used to calculate adjusted odds for each of the earlier-described measures in microsatellite stable cancers. One multivariate model adjusted for age, tumor site, AJCC stage, sex, differentiation, and histology, and the other multivariate model adjusted for all of these measures plus tumor mutations. A family history of cancer in first-degree relatives was limited to those patients who participated in the interview and therefore it was adjusted for age and evaluated independently of the other measures. CIMP high was observed in 256 of 864 tumors (29.6%). A total of 250 of the 840 colon carcinomas for which microsatellite instability data were available were CIMP high (29.8%, Table 1). A total of 762 of the cancers were microsatellite stable, and 78 were unstable. Unstable tumors were significantly more likely to be CIMP high than stable tumors (82.1% vs 24.4%, P < .0001). Representative examples of CpG island methylation in CIMP-high and CIMP-low colon cancers are shown in Figure 1.Table 1CIMP and hMLH1 Methylation in Stable and Unstable TumorsTotal N (%)Stable N (%)Unstable N (%)P valueaP value compares percent stable vs percent unstable for CIMP high and for each measure of hMLHl methylation.CIMP high250 (29.8)186 (24.4)64 (82.1)<.0001hMLHl-H methylatedbhMLHl-H refers to primers used by Herman et al17 (see Materials and Methods for description of primers).186 (21.3)121 (15.3)65 (80.2)<.0001hMLHl-P methylatedchMLHl-P refers to primers used by Park et al16 (see Materials and Methods for description of primers).74 (8.8)16 (2.1)58 (72.5)<.0001a P value compares percent stable vs percent unstable for CIMP high and for each measure of hMLHl methylation.b hMLHl-H refers to primers used by Herman et al17Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Crossref PubMed Scopus (5250) Google Scholar (see Materials and Methods for description of primers).c hMLHl-P refers to primers used by Park et al16Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar (see Materials and Methods for description of primers). Open table in a new tab hMLH1 methylation as determined by the original primers used by Herman et al17Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Crossref PubMed Scopus (5250) Google Scholar (see Materials and Methods section) was seen in 21.3% of tumors overall, 15.3% of microsatellite stable tumors (66% of which were CIMP low, data not shown in Table 1), and 80.2% of unstable tumors. hMLH1 methylation as determined by the primers used by Park et al16Park S.J. Rashid A. Lee J.H. Kim S.G. Hamilton S.R. Wu T.T. Frequent CpG island methylation in serrated adenomas of the colorectum.Am J Pathol. 2003; 162: 815-822Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar (see Patients and Methods section) was more specific for unstable tumors but less sensitive because it was seen in 2.1% of stable and 72.5% of unstable tumors. Regardless of the methylation measurement, however, significantly more hMLH1 methylation was seen in unstable tumors than in stable tumors. Examples of the relative nonspecificity of hMLH1 methylation as determined by the primers used by Herman et al17Herman J.G. Graff J.R. Myohanen S. Nelkin B.D. Baylin S.B. Methylation-specific PCR a novel PCR assay for methylation status of CpG islands.Proc Natl Acad Sci U S A. 1996; 93: 9821-9826Crossref PubMed Scopus (5250) Google Scholar for microsatellite instability and CIMP high are shown in Figure 1. The relationship between CIMP and clinicopathologic variables and tumor mutations for microsatellite stable tumors is shown in Table 2. In univariate analyses there were significant relationships with the BRAF V600E mutation, mutant KRAS2, proximal site, higher AJCC stage, increased age, poor differentiation, and mucinous histology. There was a trend toward a relationship with wild-type TP53, but this was not statistically significant. No significant relationship to sex was seen. The relationship with the BRAF V600E mutation was particularly notable because it was seen in 17.6% of CIMP-high tumors and only .5% of CIMP-low tumors (odds ratio [OR], 39.40; 95% confidence interval [CI], 11.90–130.42).Table 2Comparison of CIMP High and CIMP Low With Respect to Clinicopathologic Variables and Tumor Mutations in Microsatellite Stable TumorsCIMP lowCIMP highUnivariate model ORbOR for CIMP high status from univariate analysis. (95% CI)Adjusted model ORcModel adjusted for tumor site, AJCC stage, age, sex, differentiation, and mucinous histology; n = 567 for CIMP low, and n = 186 for CIMP high. (95% CI)Full model ORdModel adjusted as in c, and further adjusted for KRAS2, TP53, and BRAF tumor mutations; n = 503 for CIMP low, and n = 172 for CIMP high. (95% CI)naCounts within categories may not sum to total shown at top of table owing to missing data on tumor characteristics.(%)naCounts within categories may not sum to total shown at top of table owing to missing data on tumor characteristics.(%)Total57675.618624.4Tumor siteProximal22139.411967.61.001.001.00Distal34060.65732.4.31 (.22–.45).35 (.24–.51).42 (.27–.65)AJCC stage115327.02915.61.001.001.00216128.44122.01.34 (.80–2.27).92 (.53–1.62).99 (.54–1.83)315427.27339.22.50 (1.54–4.06)1.70 (1.00–2.88)1.49 (.82–2.70)49917.54323.12.29 (1.34–3.91)1.54 (.86–2.76)1.38 (.73–2.64)P trend<.0001.002.03Age, y<558614.9179.11.001.001.0055–6415326.64825.81.59 (.86–2.93)1.91 (.99–3.67)2.08 (.99–4.34)65–7014725.54725.31.62 (.87–2.99)1.85 (.96–3.56)2.04 (.97–4.25)71–7919033.07439.81.97 (1.10–3.54)2.25 (1.20–1.20)2.40 (1.20–4.82)P trend.03.03.03SexMale32055.69450.51.001.001.00Female25644.49249.51.22 (.88–1.70)1.13 (.79–1.61)1.06 (.72–1.58)DifferentiationWell5410.1126.91.001.001.00Moderate41277.211667.11.27 (.66–2.45)1.22 (.61–2.44)1.17 (.56–2.43)Poor6812.74526.02.98 (1.43–6.18)2.44 (1.11–6.37)2.21 (.94–5.18)P trend.01.03.05Mucinous histologyNo52691.315281.71.001.001.00Yes508.73418.32.35 (1.47–3.77)1.76 (1.06–2.93)1.51 (.83–2.74)KRAS2WT37668.69553.11.001.00MUT17231.48446.91.93 (1.37–2.73)2.22 (1.48–3.34)TP53WT27650.010055.91.001.00MUT27650.07944.1.79 (.56–1.11).93 (.62–1.39)BRAFWT55499.515082.41.001.00MUT30.53217.639.40 (11.90–130.42)39.52 (11.44–136.56)NOTE. CIMP low is the reference category.a Counts within categories may not sum to total shown at top of table owing to missing data on tumor characteristics.b OR for CIMP high status from univariate analysis.c Model adjusted for tumor site, AJCC stage, age, sex, differentiation, and mucinous histology; n = 567 for CIMP low, and n = 186 for CIMP high.d Model adjusted as in cModel adjusted for tumor site, AJCC stage, age, sex, differentiation, and mucinous histology; n = 567 for CIMP low, and n = 186 for CIMP high., and further adjusted for KRAS2, TP53, and BRAF tumor mutations; n = 503 for CIMP low, and n = 172 for CIMP high. Open table in a new tab NOTE. CIMP low is the reference category. A multivariate analysis then was performed using all clinicopathologic variables except tumor mutations. In this analysis all of the previous univariate relationships were seen. Finally, a multivariate analysis that included tumor mutations showed significant relationships with the BRAF V600E mutation, KRAS2 mutations, proximal location, older age, and increased stage, and nonsignificant trends toward poor differentiation and mucinous histology. Again, the relationship with the BRAF V600E mutation was highly significant (OR, 39.52; 95% CI, 11.44–136.56). The relationship between CIMP and clinicopathologic variables and tumor mutations for unstable tumors is shown in Table 3. When compared with CIMP-low unstable tumors, CIMP-high unstable tumors had significantly more BRAF V600E mutations, were more likely to be proximal, occurred in older individuals, and were less likely to have KRAS2 mutations. Individuals with unstable CIMP-high tumors also were more likely to be women and have tumors with poor differentiation, but these relationships were not statistically significant. Once again, the relationship between CIMP-high and the BRAF V600E mutation was particularly striking (OR, 9.80; 95% CI, 2.00–48.12). Multivariate analyses could not be performed in unstable tumors because of their relatively small numbers.Table 3Comparison of CIMP High With CIMP Low With Respect to Clinicopathologic Variables and Tumor Mutations in Microsatellite Unstable TumorsCIMP lowCIMP highUnivariate model ORbOdds ratio for CIMP high status from univariate analysis. (95% CI)NaCounts within categories may not sum to total shown at top of table owing to missing data on tumor characteristics.(%)NaCounts within categories may not sum to total shown at top of table owing to missing data on tumor characteristics.(%)Total1417.96482.1Tumor siteProximal750.05793.41.00Distal750.046.6.07 (.02–.30)AJCC stagecStages 3 and 4 were combined in the calculation of the ORs owing to small cell size.1321.41015.91.002428.62539.71.87 (.35–9.93)3750.02336.51.20 (.26–5.56)40.057.9P trend.99Age<55535.7812.51.0055–64214.3710.92.19 (.32–15.04)65–70428.61523.42.34 (.49–11.27)71–79321.43453.17.08 (1.39–35.98)P trend.02SexMale857.12640.61.00Female642.93859.41.95 (.60–6.28)DifferentiationdWell and moderate differentiation were combined in the calculation of the ORs owing to small cell size.Well17.123.3Moderate964.33050.01.00Poor428.62846.72.19 (.62–7.76)P trend.10Mucinous histologyNo857.14469.81.00Yes642.91930.

Colorectal cancer is a major public health problem in both North America and western Europe, and incidence and mortality rates are rapidly increasing in many previously low-risk countries. It has been hypothesized that increased intakes of fiber, vitamin C, and beta carotene could decrease the risk of colorectal cancer.The objective of this study was to examine the effects of fiber, vitamin C, and beta-carotene intakes on colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. The study was designed to estimate risks in the pooled data, to test the consistency of the associations across the studies, and to examine interactions of the effects of the nutrients with cancer site, sex, and age.Original data records for 5287 case subjects with colorectal cancer and 10,470 control subjects without disease were combined. Logistic regression analysis was used to estimate relative risks and confidence intervals for intakes of fiber, vitamin C, and beta carotene, with the effects of study, sex, and age group being adjusted by stratification.Risk decreased as fiber intake increased; relative risks were 0.79, 0.69, 0.63, and 0.53 for the four highest quintiles of intake compared with the lowest quintile (trend, P < .0001). The inverse association with fiber is seen in 12 of the 13 studies and is similar in magnitude for left- and right-sided colon and rectal cancers, for men and for women, and for different age groups. In contrast, after adjustment for fiber intake, only weak inverse associations are seen for the intakes of vitamin C and beta carotene.This analysis provides substantive evidence that intake of fiber-rich foods is inversely related to risk of cancers of both the colon and rectum.If causality is assumed, we estimate that risk of colorectal cancer in the U.S. population could be reduced about 31% (50,000 cases annually) by an average increase in fiber intake from food sources of about 13 g/d, corresponding to an average increase of about 70%.

Consumption of plant foods and dairy and meat products may moderate increases in blood pressure.The objective was to evaluate associations of dietary intake with the 15-y incidence of elevated blood pressure (EBP; ie, incident systolic BP >or= 130 mm Hg, diastolic BP >or= 85 mm Hg, or use of antihypertensive medication).Proportional hazards regression was used to evaluate relations of dietary intake at years 0 and 7 with the 15-y incidence of EBP in the Coronary Artery Risk Development in Young Adults (CARDIA) Study of 4304 participants aged 18-30 y at baseline.EBP incidence varied from 12% in white women to 33% in black men. Plant food intake (whole grains, refined grains, fruit, vegetables, nuts, or legumes) was inversely related to EBP after adjustment for age, sex, race, center, energy intake, cardiovascular disease risk factors, and other potential confounding factors. Compared with quintile 1, the relative hazards of EBP for quintiles 2-5 of plant food intake were 0.83 (95% CI: 0.68, 1.01), 0.83 (0.67, 1.02), 0.82 (0.65, 1.03), and 0.64 (0.53, 0.90), respectively; P for trend = 0.01. Dairy intake was not related to EBP (P for trend = 0.06), and positive dose-response relations for EBP were observed across increasing quintiles of meat intake (P for trend = 0.004). In subgroup analyses, risk of EBP was positively associated with red and processed meat intake, whereas it was inversely associated with intakes of whole grain, fruit, nuts, and milk. Adjustment for intermediary factors in the causal pathway attenuated these relations.These findings are consistent with a beneficial effect of plant food intake and an adverse effect of meat intake on blood pressure.

Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

Guidelines for initiating colorectal cancer (CRC) screening are based on family history but do not consider lifestyle, environmental, or genetic risk factors. We developed models to determine risk of CRC, based on lifestyle and environmental factors and genetic variants, and to identify an optimal age to begin screening.We collected data from 9748 CRC cases and 10,590 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colorectal Transdisciplinary study, from 1992 through 2005. Half of the participants were used to develop the risk determination model and the other half were used to evaluate the discriminatory accuracy (validation set). Models of CRC risk were created based on family history, 19 lifestyle and environmental factors (E-score), and 63 CRC-associated single-nucleotide polymorphisms identified in genome-wide association studies (G-score). We evaluated the discriminatory accuracy of the models by calculating area under the receiver operating characteristic curve values, adjusting for study, age, and endoscopy history for the validation set. We used the models to project the 10-year absolute risk of CRC for a given risk profile and recommend ages to begin screening in comparison to CRC risk for an average individual at 50 years of age, using external population incidence rates for non-Hispanic whites from the Surveillance, Epidemiology, and End Results program registry.In our models, E-score and G-score each determined risk of CRC with greater accuracy than family history. A model that combined both scores and family history estimated CRC risk with an area under the receiver operating characteristic curve value of 0.63 (95% confidence interval, 0.62-0.64) for men and 0.62 (95% confidence interval, 0.61-0.63) for women; area under the receiver operating characteristic curve values based on only family history ranged from 0.53 to 0.54 and those based only E-score or G-score ranged from 0.59 to 0.60. Although screening is recommended to begin at age 50 years for individuals with no family history of CRC, starting ages calculated based on combined E-score and G-score differed by 12 years for men and 14 for women, for individuals with the highest vs the lowest 10% of risk.We used data from 2 large international consortia to develop CRC risk calculation models that included genetic and environmental factors along with family history. These determine risk of CRC and starting ages for screening with greater accuracy than the family history only model, which is based on the current screening guideline. These scoring systems might serve as a first step toward developing individualized CRC prevention strategies.

Abstract Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER +ve ) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Known genetic loci explain only a small proportion of the familial relative risk of colorectal cancer (CRC). We conducted a genome-wide association study of CRC in East Asians with 14,963 cases and 31,945 controls and identified 6 new loci associated with CRC risk (P = 3.42 × 10(-8) to 9.22 × 10(-21)) at 10q22.3, 10q25.2, 11q12.2, 12p13.31, 17p13.3 and 19q13.2. Two of these loci map to genes (TCF7L2 and TGFB1) with established roles in colorectal tumorigenesis. Four other loci are located in or near genes involved in transcriptional regulation (ZMIZ1), genome maintenance (FEN1), fatty acid metabolism (FADS1 and FADS2), cancer cell motility and metastasis (CD9), and cell growth and differentiation (NXN). We also found suggestive evidence for three additional loci associated with CRC risk near genome-wide significance at 8q24.11, 10q21.1 and 10q24.2. Furthermore, we replicated 22 previously reported CRC-associated loci. Our study provides insights into the genetic basis of CRC and suggests the involvement of new biological pathways.

IMPORTANCEUse of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTSCase-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011.Participants were all of European descent.EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES Colorectal cancer.RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74];P = 6.2 × 10 -28 ) compared with nonregular use.In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10 -9 for interaction).Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70];P = 7.7 × 10 -33 ) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81];P = .002).In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10 -9 for interaction).Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71];P = 1.9 × 10 -30 ) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20];P = .76). CONCLUSIONS AND RELEVANCEIn this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15.Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

Accurate colorectal cancer (CRC) risk prediction models are critical for identifying individuals at low and high risk of developing CRC, as they can then be offered targeted screening and interventions to address their risks of developing disease (if they are in a high-risk group) and avoid unnecessary screening and interventions (if they are in a low-risk group). As it is likely that thousands of genetic variants contribute to CRC risk, it is clinically important to investigate whether these genetic variants can be used jointly for CRC risk prediction. In this paper, we derived and compared different approaches to generating predictive polygenic risk scores (PRS) from genome-wide association studies (GWASs) including 55,105 CRC-affected case subjects and 65,079 control subjects of European ancestry. We built the PRS in three ways, using (1) 140 previously identified and validated CRC loci; (2) SNP selection based on linkage disequilibrium (LD) clumping followed by machine-learning approaches; and (3) LDpred, a Bayesian approach for genome-wide risk prediction. We tested the PRS in an independent cohort of 101,987 individuals with 1,699 CRC-affected case subjects. The discriminatory accuracy, calculated by the age- and sex-adjusted area under the receiver operating characteristics curve (AUC), was highest for the LDpred-derived PRS (AUC = 0.654) including nearly 1.2 M genetic variants (the proportion of causal genetic variants for CRC assumed to be 0.003), whereas the PRS of the 140 known variants identified from GWASs had the lowest AUC (AUC = 0.629). Based on the LDpred-derived PRS, we are able to identify 30% of individuals without a family history as having risk for CRC similar to those with a family history of CRC, whereas the PRS based on known GWAS variants identified only top 10% as having a similar relative risk. About 90% of these individuals have no family history and would have been considered average risk under current screening guidelines, but might benefit from earlier screening. The developed PRS offers a way for risk-stratified CRC screening and other targeted interventions.

<h3>Background & Aims</h3> Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. <h3>Methods</h3> We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. <h3>Results</h3> Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (<i>P</i> for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28–4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80–3.04). This association was strongest for participants without a first-degree family history of CRC (<i>P</i> for interaction = 5.61 × 10^–5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61–5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70–3.00). Sensitivity analyses were consistent with these findings. <h3>Conclusions</h3> In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies. A multi-ancestry genome-wide association study meta-analysis, combined with transcriptome- and methylome-wide association analyses, identifies risk loci associated with colorectal cancer. Credible effector genes and their target tissues are also highlighted, showing that over a third probably act outside the colonic mucosa.

Microsatellite instability (MSI) has been reported to occur in approximately 10%-15% of colon tumors. MSI is characterized by the presence of mutations in tandemly repeated DNA sequences known as microsatellites. Some individuals with unstable tumors have inherited mutations in mismatch repair genes, but MSI is also observed in sporadic colon cancer. It is unknown whether lifestyle factors associated with colon cancer, such as physical activity, body size, cigarette smoking, or use of aspirin and/or nonsteroidal anti-inflammatory drugs, contribute to MSI in sporadic tumors.Data from a population-based, case-control study of colon cancer were used. Case subjects were between 30 and 79 years of age at the time of diagnosis and included both men and women. Questionnaire data were used to obtain information on lifestyle factors. Tumor MSI was determined with the use of a panel of 10 tetranucleotide repeats and two mononucleotide repeats. A total of 1510 case subjects had valid questionnaire data and tumor DNA from which we were able to obtain MSI status. Questionnaire data were compared with lifestyle factors reported by 2410 population-based control subjects. All statistical tests were two-sided.MSI-positive (MSI(+)) tumors were most common in older people and women and in the proximal colon. Patients with MSI(+) tumors were more likely to smoke 20 or more cigarettes a day than case subjects with MSI-negative (MSI(-)) tumors (odds ratio for being a smoker = 1.6 [95% confidence interval = 1.0-2.5] for men and 2.2 [95% confidence interval = 1.4-3.5] for women). The association between MSI(+) tumors and cigarette smoking was strongest among case subjects who started to smoke at a young age, smoked for 35 or more years, and were either current smokers or had stopped fewer than 15 years before diagnosis. A statistically significant linear trend of increased risk of MSI(+) tumors was observed with increasing amount smoked (P<.01).This study suggests that smoking cigarettes statistically significantly contributes to MSI in colon tumors. We estimate that approximately 21% of MSI in colon tumors may be attributable to cigarette smoking.

Background: Carotenoids have numerous biological properties that may underpin a role for them as chemopreventive agents. However, except for β-carotene, little is known about how dietary carotenoids are associated with common cancers, including colon cancer.

The authors linked interview data drawn from Utah participants in the Diet, Activity, and Reproduction in Colon Cancer (DARCC) Study (1992-1995) to genealogic and cancer information contained in the Utah Population Database (UPDB). They evaluated the sensitivity of subjects' reports of familial cancers and measured the overall agreement between reported and database records with the kappa (kappa) statistic. They calculated odds ratios from logistic regression to compare the relative risk estimates that would result from use of either data set (or both data sets). Overall, 37.6% (331 of 881) of the Utah DARCC subjects were linked to the UPDB genealogy. High sensitivities were observed for subjects' reports of breast (83%), colorectal (73%), and prostate (70%) cancers, while ovarian (60%) and uterine (30%) cancers were not reported as well. Results for kappa were similar, with values of 0.63 for breast cancer and 0.56 for colorectal cancer. Although the observed kappa s of 0.36 and 0.25 for ovarian and uterine cancers, respectively, exceeded chance expectations, the agreement between subjects' reports and database records was unimpressive. No consistent difference was observed between cases and controls in the accuracy of self-reports. In general, higher sensitivities were observed among younger subjects than older subjects; females reported family histories of cancer only slightly better than males. A college education was not consistently associated with more accurate reporting of family history of cancer. These results indicate that subjects in a case-control study are able to report accurately family histories of several common kinds of cancer and that they can do so without observable recall bias. The accuracy of self-reports may not be adequate for reproductive tract cancers and cancers such as rectal cancer that are frequently confused with cancers of similar organs.

To meet the objectives for dietary assessment in the Coronary Artery Risk Development in Young Adults (CARDIA) prospective study, we developed a dietary history to provide accurate and reliable quantitative data on habitual individual nutrient intakes at baseline. The CARDIA dietary history was an interviewer-administered method that included a short questionnaire regarding general dietary practices followed by a comprehensive food frequency questionnaire about typical intake of foods using the previous month as a reference for recall. For each broad category of foods, participants were questioned in detail about specific foods only if they indicated that they consumed foods from that category. Follow-up questions for selected foods concerned serving size, frequency of consumption, and common additions to these foods. Provision was made for reporting foods not found in the food frequency list. The interview took approximately 45 minutes. Cue cards prompted responses and plastic food models assisted in estimating usual amounts consumed. A precoded format standardized coding for reported items and established the detail needed for recall during the interview. Baseline nutrient analyses from the CARDIA dietary history provided estimates that agreed reasonably well with expected caloric intake for body mass index according to the age- and sex-specific Recommended Dietary Allowances, but were higher than those reported from 24-hour recalls for comparable age, sex, and race groups in the second National Health and Nutrition Examination Survey. The CARDIA dietary history is a comprehensive assessment tool that can provide a dietitian with detailed information regarding habitual eating patterns and nutrient intakes among adults.

Cigarette smoking has been associated with microsatellite instability in sporadic colon cancer. Most microsatellite-unstable colon cancers have widespread methylation of CpG islands (i.e., the CpG island methylator phenotype [CIMP]), and many of these tumors harbor the V600E BRAF mutation. We investigated whether the association between smoking and all colon cancers could be explained through induction of CIMP and/or BRAF mutations.We evaluated 1315 case patients with colon cancer and 2392 control subjects in a population-based study. Demographic information, including smoking history, was obtained in an interview. Microsatellite instability was determined primarily by evaluation of the mononucleotide repeat BAT-26. CIMP was determined by sodium bisulfite modification of DNA followed by methylation-specific polymerase chain reaction amplification of CpG islands in hMLH1, p16, and MINTS1, -2, and -31. Tumors were scored as CIMP high (i.e., > or = 2 CpG islands methylated) or CIMP low (i.e., < 2 CpG islands methylated). BRAF V600E mutations were identified by sequencing. Logistic regression was used to quantify relationships among smoking, CIMP, and BRAF. All statistical tests were two-sided.Heavy smoking (i.e., > 20 cigarettes per day), compared with nonsmoking, was associated with an increased risk of CIMP-high colon cancer (odds ratio [OR] = 2.06, 95% confidence interval [CI] = 1.43 to 2.97) and also with BRAF V600E mutations (OR = 3.16, 95% CI = 1.80 to 5.54). The association between cigarette smoking and the risk of colon cancer was limited to the minority of tumors that were CIMP high and BRAF wild type or CIMP high and BRAF mutated (for heavy smokers, OR = 1.91, 95% CI = 1.23 to 2.97, and OR = 2.85, 95% CI = 1.53 to 5.29, respectively). All relationships above showed a statistically significant relationship to amount smoked (P(trend) < .001 for all, except that relationship with tumors that were CIMP high and BRAF wild type, for which P(trend) = .008) and were independent of microsatellite instability.Previously identified associations between smoking and colon cancer, whether microsatellite unstable or stable, appear to be explained by the association of smoking with CIMP and BRAF mutations.

Estimates of the frequency of hereditary nonpolyposis colon cancer (HNPCC) based on clinical criteria have varied widely. Recent studies of germline mismatch repair gene mutations have suggested that HNPCC accounts for close to 3% of all colon cancer, but this estimate may have been inflated by inclusion of founder effects peculiar to Finland. We therefore determined by genetic criteria the colon cancer burden associated with HNPCC in a population-based study of 1066 individuals from Utah and California.The coding regions of mismatch repair genes hMSH2 and hMLH1 were sequenced from the germline of those individuals whose tumors exhibited microsatellite instability.Microsatellite instability was present in 16% (171/1066) of tumors. Pathogenic germline mismatch repair gene mutations were identified in 7 individuals, and missense amino acid changes of uncertain significance were identified in another 6 individuals. After adjusting for the availability of sufficient germline DNA for sequencing, the 7 clearly pathogenic mutations accounted for 0.86% of colon cancer at the population level. Individuals with these mutations were significantly younger, more likely to have a family history of colon and endometrial cancer, and more likely to have first-degree relatives with a young-age onset of colon cancer than individuals with unstable tumors but without germline mutations (P < 0.01).We conclude that genetically defined HNPCC accounts for a very small percentage of colon cancer at the population level, a percentage less than that estimated by most previous clinical studies.

Given the high incidence of colorectal cancer (CRC), and the availability of procedures that can detect disease and remove precancerous lesions, there is a need for a model that estimates the probability of developing CRC across various age intervals and risk factor profiles.The development of separate CRC absolute risk models for men and women included estimating relative risks and attributable risk parameters from population-based case-control data separately for proximal, distal, and rectal cancer and combining these estimates with baseline age-specific cancer hazard rates based on Surveillance, Epidemiology, and End Results (SEER) incidence rates and competing mortality risks.For men, the model included a cancer-negative sigmoidoscopy/colonoscopy in the last 10 years, polyp history in the last 10 years, history of CRC in first-degree relatives, aspirin and nonsteroidal anti-inflammatory drug (NSAID) use, cigarette smoking, body mass index (BMI), current leisure-time vigorous activity, and vegetable consumption. For women, the model included sigmoidoscopy/colonoscopy, polyp history, history of CRC in first-degree relatives, aspirin and NSAID use, BMI, leisure-time vigorous activity, vegetable consumption, hormone-replacement therapy (HRT), and estrogen exposure on the basis of menopausal status. For men and women, relative risks differed slightly by tumor site. A validation study in independent data indicates that the models for men and women are well calibrated.We developed absolute risk prediction models for CRC from population-based data, and a simple questionnaire suitable for self-administration. This model is potentially useful for counseling, for designing research intervention studies, and for other applications.

Seventeen to 20 years of mortality follow-up were used to study the relation of leisure time physical activity (LTPA) to coronary heart disease mortality and to all-cause mortality in white male US railroad workers (n = 3,043). This cohort was initially examined from 1957 to 1960, reexamined from 1962 to 1964, and followed until 1977 or death. LTPA was ascertained by a precursor of the Minnesota Leisure Time Physical Activity Questionnaire. The risk estimate for coronary heart disease death, after adjusting for age, was 1.39 for sedentary men who expended 40 kcal/wk in LTPA compared with very active men who expended 3,632 kcal/wk. This relation was attenuated by adjusting for other coronary heart disease risk factors, but it remained independent and significant. Caloric expenditure in light and moderate activity, as well as that performed in any intense activity, showed independent relations to cardiovascular death and all-cause mortality. Associations were slightly stronger in occupationally sedentary men. These results support the hypothesis that physical activity protects against death from coronary heart disease and all-cause mortality.

We examined the association between body mass index (BMI) around the time of diagnosis, weight change post-diagnosis, and breast cancer prognosis in a prospective cohort study of 1,692 breast cancer survivors. Pre-diagnosis weight, weight at study entry, and height was obtained from mailed questionnaires and then weight change and BMI were calculated. After approximately seven years of follow-up, 207 recurrences, 99 deaths due to breast cancer, and 162 deaths due to any cause were reported. Delayed entry Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), controlling for treatment and known prognostic factors. Being obese one year before diagnosis was associated with an increased risk of death from any cause (HR = 1.6; 95% CI: 1.1–2.3) and a suggestion of increased risk of death from breast cancer (HR = 1.6; 95% CI: 0.9–2.7). However, weight gain up to four years after a breast cancer diagnosis was not associated with an increased risk of recurrence or death from any cause nor did moderate weight loss (5–10%) decrease risk of these outcomes. There was some evidence that women who had larger weight losses (≥10%) between pre-diagnosis and study entry had an increased risk of recurrence (HR = 1.7; 95% CI 1.0–2.6) and death due to any cause (HR = 2.1; 95% CI 1.3–3.4) compared to being weight stable. This elevated risk was more pronounced among women who were obese before diagnosis (BMI ≥ 30 kg/m2) or who had ER− or PR− tumors. We found that being obese before breast cancer diagnosis was associated with increased risk of recurrence and poorer survival, corroborating results from previous studies. However, weight gain after diagnosis did not confer additional risk. Body weight pre-diagnosis appears to be the strongest predictor of an adverse breast cancer prognosis.

Individuals with different forms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, carriers of the C677T mutation versus wild type, show differences in enzyme levels; these differences have been hypothesized to be related to DNA methylation and, perhaps, to the nucleotide pool size. Using data from an incident case-control study, we evaluated the combined effect of dietary intake of folate, methionine, vitamin B6, vitamin B12, and alcohol and various forms of the MTHFR gene on risk of colon cancer. Individuals homozygous for the variant form of the MTHFR gene (TT) had a slightly lower risk of colon cancer than did individuals who were wild type [CC, odds ratio (OR) = 0.8, 95% confidence interval (CI) = 0.6-1.1 for men; and OR = 0.9, 95% CI = 0.6-1.2 for women]. High levels of intake of folate, vitamin B6, and vitamin B12 were associated with a 30-40% reduction in risk of colon cancer among those with the TT relative to those with low levels of intake who were CC genotype. Associations were stronger for proximal tumors, in which high levels of intake of these nutrients were associated with a halving of risk among those with the TT genotype. The inverse association with high levels of these nutrients in those with the TT genotype was stronger among those diagnosed at an older age. Although imprecise, the inverse association with the low-risk diet that was high in folate and methionine and without alcohol was observed for both the TT genotype (OR = 0.4 95% CI = 0.1-0.9) and the CC/CT genotype (OR = 0.6, 95% CI = 0.4-1.0), but this association was not seen with the high-risk diet for either the TT or CC/CT genotype. Although associations were generally weak, these findings suggest that those with differing MTHFR genotypes may have different susceptibilities to colon cancer, based on dietary consumption of folate, vitamin B6, and vitamin B12.

Journal Article Comparison of Two Methods of Assessing Physical Activity in the Coronary Artery Risk Development in Young Adults (CARDIA) Study Get access Stephen Sidney, Stephen Sidney 1Division of Research, Kaiser Permanente Medical Care Program (Northern California Region)Oakland, CA Reprint requests to Dr. Stephen Sidney, Division of Research, Kaiser Permanente Medical Care Program, 3451 Piedmont Avenue, Oakland, CA 94611. Search for other works by this author on: Oxford Academic PubMed Google Scholar David R. Jacobs, Jr., David R. Jacobs, Jr. 2Division of Epidemiology, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar William L. Haskell, William L. Haskell 3Stanford Center for Research in Disease Prevention, Stanford UniversityStanford, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar Mary Anne Armstrong, Mary Anne Armstrong 1Division of Research, Kaiser Permanente Medical Care Program (Northern California Region)Oakland, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar Albert Dimicco, Albert Dimicco 4Cooper Green HospitalBirmingham, AL Search for other works by this author on: Oxford Academic PubMed Google Scholar Albert Oberman, Albert Oberman 5Behavior Medicine Unit, Division of General and Preventive Medicine, University of AlabamaBirmingham, AL Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter J. Savage, Peter J. Savage 6National Heart, Lung, and Blood InstituteBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar Martha L. Slattery, Martha L. Slattery 7Department of Family and Community Medicine, University of Utah Medical SchoolSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar Barbara Sternfeld, Barbara Sternfeld 1Division of Research, Kaiser Permanente Medical Care Program (Northern California Region)Oakland, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar Linda Van Hom Linda Van Hom 8Department of Community Health and Preventive Medicine, Northwestern University Medical SchoolChicago, IL Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 133, Issue 12, 15 June 1991, Pages 1231–1245, https://doi.org/10.1093/oxfordjournals.aje.a115835 Published: 15 June 1991 Article history Received: 11 April 1990 Revision received: 26 November 1990 Published: 15 June 1991

Journal Article DIETARY INTAKE AND COLON CANCER: SEX- AND ANATOMIC SITE-SPECIFIC ASSOCIATIONS Get access DEE W. WEST, DEE W. WEST 1Northern California Cancer CenterBelmont, CA2Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Reprint requests to Dr. Dee W West, Northern California Cancer Center, 1301 Shoreway Road, Suite 425, Belmont, CA 94002 Search for other works by this author on: Oxford Academic PubMed Google Scholar MARTHA L. SLATTERY, MARTHA L. SLATTERY 2Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar LINDA M. ROBISON, LINDA M. ROBISON 2Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar KATHARINA L. SCHUMAN, KATHARINA L. SCHUMAN 3Department of Health, Portland State UniversityPortland, OR Search for other works by this author on: Oxford Academic PubMed Google Scholar MARILYN H. FORD, MARILYN H. FORD 2Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar ARTHUR W. MAHONEY, ARTHUR W. MAHONEY 4Department of Nutrition and Food Sciences, Utah State UniversityLogan, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar JOSEPH L. LYON, JOSEPH L. LYON 2Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar ANN W. SORENSEN ANN W. SORENSEN 5Geriatrics Branch, National Institute on Aging, National Institutes of HealthBethesda, MD Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 130, Issue 5, November 1989, Pages 883–894, https://doi.org/10.1093/oxfordjournals.aje.a115421 Published: 01 November 1989 Article history Received: 26 February 1988 Revision received: 10 April 1989 Published: 01 November 1989

Cross-sectional associations between body fat and its distribution and environmental factors influencing energy balance were examined in 5115 young adults. Protein was directly associated with body mass index (BMI) in all race and sex groups (P < 0.01) after age, education, cigarette-smoking status, alcohol intake, and physical activity were adjusted for. Carbohydrate intake was inversely associated with BMI in males (P = 0.02). Total physical activity was inversely associated with BMI in white women and with skinfold-thickness measures (P < 0.01) in all groups. Waist-to-hip-circumference ratio (WHCR) was positively associated with total kilojoules (kilocalories) in women, inversely associated with percent of kilojoules (kilocalories) from carbohydrates in whites, grams of crude fiber/4184 kJ (1000 kcal) (except in black men), and physical activity (except in white women). WHCR was directly associated with cigarette smoking except in black men, and with total alcohol intake in men. Beer was consistently associated with WHCR in all race and sex groups.

A population-based case-control study was used to assess the relations of physical activity and diet to the development of colon cancer in Utah. Data were obtained for a reference period of two years prior to interview for controls (204 females and 180 males) and two years prior to the date of diagnosis for cases (119 females and 110 males). Both leisure time and occupational activities were ascertained by level of intensity and were converted to calories expended per week for analysis. Dietary data were obtained from a quantitative food frequency questionnaire. Physical activity and dietary data were divided into quartiles based upon the distribution in the study population for analyses. Total physical activity was protective against the development of colon cancer for both males (odds ratio (OR) = 0.70) and females (OR = 0.48) when high and low quartiles of activity were compared. Intense physical activity was the component of activity that had the greatest protective effect for males (OR = 0.27); a similar relation was seen for females (OR = 0.55). The observed relation between physical activity and colon cancer was not confounded by dietary intake of calories, fat, or protein, nor was the diet and colon cancer relation confounded by physical activity (odds ratios for calories, protein, and fat in males were 2.40, 2.57, and 2.18, respectively). Assessment of the interrelations among physical activity, diet, and colon cancer suggests that physical activity modifies colon cancer risk associated with diet.

Family history of colon cancer has been shown to be related to the risk of developing colon cancer. The impact that a comprehensive family history of colon or other cancers has on the risk of colon cancer has not been thoroughly studied.The purpose of this study was to assess the risk of developing colon cancer associated with having a family history of colon, rectal, breast, ovarian, endometrial, or prostate cancer.A case-control study was conducted using data from the Utah Population Database. Case patients had first primary colon cancers (n = 2543). Three control subjects per case were individually matched to case patients on year of birth, place of birth, marital status, and sex.Those case patients with the highest familial standardized incidence ratio were at an increased risk of developing colon cancer (for men, odds ratio [OR] = 2.51 and 95% confidence interval [CI] = 1.88-3.29; for women, OR = 2.90 and 95% CI = 2.17-3.82). A second- or third-degree relative with colon cancer increased risk from 25% to 52%. Risk associated with family history was greater in those patients diagnosed before age 50 (for men, OR = 3.61 and for women, OR = 7.18) than in those diagnosed at 50 or more years of age (for men, OR = 2.44 and for women, OR = 2.73). The risk associated with a family history of colon cancer was greatest for the distal segment of the colon. Women were at an increased risk of colon cancer if they had a first-degree relative with breast (OR = 1.59; 95% CI = 1.25-2.03), uterine (OR = 1.50; 95% CI = 0.99-2.26), ovarian (OR = 1.63; 95% CI = 1.41-1.89), or prostate (OR = 1.49; 95% CI = 1.21-1.82) cancer; men were at increased risk of colon cancer if they had a first-degree relative with breast (OR = 1.30; 95% CI = 1.02-1.66), uterine (OR = 1.96; 95% CI = 1.34-2.87), or ovarian (OR = 1.59; 95% CI = 0.90-2.81) cancer.These findings support previous observations that people with a family history of colon cancer are at increased risk of colon cancer. Those with a second- or third-degree relative with colon cancer or a first-degree relative with breast, ovarian, uterine, or prostate cancer also have an increased risk of developing colon cancer.These data support the recommendations that individuals who have a first-degree, and possibly a second- or third-degree, relative with colon cancer should have regular screening for colon cancer.

Identifying modifiable factors that reduce the risk of recurrence and improve survival in breast cancer survivors is a pressing concern. The purpose of this study was to examine the association of physical activity following diagnosis and treatment with the risk of breast cancer recurrence and mortality and all-cause mortality in women with early-stage breast cancer.The sample consisted of 1,970 women from the Life After Cancer Epidemiology study, a prospective investigation of behavioral risk factors and health outcomes. Self-reported frequency and duration of work-related, household and caregiving, recreational, and transportation-related activities during the six months prior to enrollment were assessed. Outcomes were ascertained from electronic or paper medical charts. Hazard ratios and 95% confidence intervals were estimated from delayed entry Cox proportional hazards models.Although age-adjusted results suggested that higher levels of physical activity were associated with reduced risk of recurrence and breast cancer mortality (P for trend = 0.05 and 0.07, respectively for highest versus lowest level of hours per week of moderate physical activity), these associations were attenuated after adjustment for prognostic factors and other confounding variables (P for trend = 0.36 and 0.26). In contrast, a statistically significant protective association between physical activity and all-cause mortality remained in multivariable analyses (hazard ratio, 0.66; 95% confidence interval, 0.42-1.03; P for trend = 0.04).These findings do not support a protective effect of physical activity on breast cancer recurrence or mortality but do suggest that regular physical activity is beneficial for breast cancer survivors in terms of total mortality.

Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8%versus 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats. Some studies have shown an inverse relationship between microsatellite instability in colon cancer and mutations in p53 and K-ras, whereas others have not. We therefore evaluated these features in a population-based sample of 496 individuals with colon cancer. Microsatellite instability was determined by a panel of 10 tetranucleotide repeats, the Bethesda consensus panel of mono- and dinucleotide repeats, and coding mononucleotide repeats in transforming growth factor-beta receptor type II, hMSH3, BAX, hMSH6, and insulin-like growth factor receptor type II. Mutations in codons 12 and 13 in K-ras were evaluated by sequencing. p53 overexpression (as detected by immunohistochemistry) was used as an indicator of p53 mutation; this was evaluated in 275 of the tumors. K-ras mutations were present in 33.2% of tumors, p53 overexpression in 51.5%, and microsatellite instability (as determined by the Bethesda consensus panel) in 12.5%. K-ras mutations were significantly less common in unstable tumors than stable tumors (11.8%versus 36.9%, P < 0.001). p53 overexpression was significantly less common in unstable tumors than stable tumors (20.0% versus 55.7%, P < 0.001). These inverse relationships between microsatellite instability and ras gene mutations and p53 overexpression were shown to be independent of tumor site in logistic regression analyses. All other measures of instability also showed statistically significant inverse relationships independent of tumor site with alterations in ras and p53, and instability results determined by the panel of 10 tetranucleotide repeats were highly significantly related to those determined by the Bethesda consensus panel. Coding mononucleotide repeat mutations were significantly more common in unstable tumors than stable tumors (85.7% versus 1.0%, P < 0.001). We conclude that there is an inverse relationship between microsatellite instability and mutations in p53 and K-ras, and that the molecular profile of colon cancers with microsatellite instability is characterized by relatively infrequent mutations in K-ras and p53 and relatively frequent mutations in coding mononucleotide repeats. The relationship between microsatellite instability and mutations in p53 and K-ras in colon cancer is somewhat controversial. Some studies have shown an inverse relationship between instability and mutations in these genes, whereas other studies have not.1Fujiwara T Stolker JM Watanabe T Rashid A Longo P Eshleman J Booker S Lynch HT Jass JR Green JS Kim H Jen J Vogelstein B Hamilton SR Accumulated clonal genetic alterations in familial and sporadic colorectal carcinomas with widespread instability in microsatellite sequences.Am J Pathol. 1998; 153: 1063-1078Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar Possible explanations for these inconsistent results include small studies with insufficient power to show a significant relationship, studies of different populations, and/or different methods for measuring microsatellite instability. In addition, most previous studies did not control for tumor site, a potentially confounding variable because of the high correlation between microsatellite instability and proximal tumor location.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar The above concerns are addressed in the current study by evaluating microsatellite instability, K-ras, and p53 in a large, population-based sample of colon cancers from the state of Utah. Microsatellite instability is analyzed in several different ways: a panel of 10 tetranucleotide repeats used by us in previous studies,2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 3Samowitz WS Slattery ML Microsatellite instability in colorectal adenomas.Gastroenterology. 1997; 112: 1515-1519Abstract Full Text PDF PubMed Scopus (57) Google Scholar, 4Samowitz WS Slattery ML Transforming growth factor β receptor type 2 mutations and microsatellite instability in sporadic colorectal adenomas and carcinomas.Am J Pathol. 1997; 151: 33-35PubMed Google Scholar the Bethesda consensus panel generated by a National Cancer Institute workshop on microsatellite instability,5Boland CR Thibodeau SN Hamilton SR Sidransky D Eshleman JR Burt RW Meltzer SJ Rodriguez-Bigas MA Fodde R Ranzani N Srivastava S A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res. 1998; 58: 5248-5257PubMed Google Scholar and mononucleotide repeats within the coding regions of transforming growth factor-β receptor type II (TGFβRII), BAX, hMSH3, hMSH6, and the insulin-like growth factor type II receptor (IGFIIR).6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar We also determine whether relationships between microsatellite instability and alterations in ras and p53 are independent of tumor site (and other variables) in logistic regression analyses. Molecular analysis of colon cancer samples from 496 individuals was performed. These individuals represent the Utah portion of a population-based case-control study of the etiology of colon cancer7Slattery ML Potter JD Caan BJ Edwards SL Coates A Ma K-N Berry TD Energy balance and colon cancer: beyond physical activity.Cancer Res. 1997; 57: 75-80PubMed Google Scholar and includes 154 individuals previously evaluated in a study of microsatellite instability and family history.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar Study participants were from an eight county area in Utah (Davis, Salt Lake, Utah, Weber, Wasatch, Tooele, Morgan, and Summit counties). Eligibility criteria included diagnosis with first-primary incident colon cancer (ICD-O second edition codes 18.0, 18.2 to 18.9) between October 1, 1991, and September 30, 1994, age between 30 and 79 years at time of diagnosis, and mentally competent to complete the interview. Individuals with adenomatous polyposis coli or inflammatory bowel disease were excluded from the study. Individuals with hereditary nonpolyposis colon cancer were not specifically excluded, but such individuals should comprise only a small fraction of those with colon cancer at the population level;8Aaltonen LA Salovaara R Kristo P Canzian F Hemminki A Peltomaki P Chadwick RB Kaariainen H Eskelinen M Jarvinen H Mecklin J-P de la Chapelle A Incidence of hereditary nonpolyposis colorectal cancer and feasibility of molecular screening for the disease.N Engl J Med. 1998; 338: 1481-1487Crossref PubMed Scopus (989) Google Scholar this study sample therefore consists mostly of individuals with sporadic colon cancer. The 496 individuals represent 85.8% (496 of 578) of those diagnosed with colon cancer in the state of Utah between October, 1991, and October, 1994, again underscoring the population-based nature of this study. Colon cancer tissue was microdissected and DNA extracted from formalin-fixed paraffin-embedded tissue blocks as described previously.9Spirio LN Samowitz WS Robertson J Robertson M Burt RW Leppert MF White R Alleles of APC modulate the frequency and classes of mutations that lead to colon polyps.Nat Genet. 1998; 20: 385-388Crossref PubMed Scopus (126) Google Scholar The respective normal DNA from each individual was extracted from peripheral blood (222 cases) or from paraffin blocks of normal colonic mucosa (274 cases). Each tumor was evaluated for microsatellite instability with a panel of 10 tetranucleotide repeats2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar and with the Bethesda consensus panel (mononucleotide repeats BAT-25 and BAT-26 and dinucleotide repeats D5S346, D2S123, and D17S250) generated by the National Cancer Institute workshop on microsatellite instability.5Boland CR Thibodeau SN Hamilton SR Sidransky D Eshleman JR Burt RW Meltzer SJ Rodriguez-Bigas MA Fodde R Ranzani N Srivastava S A National Cancer Institute workshop on microsatellite instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer.Cancer Res. 1998; 58: 5248-5257PubMed Google Scholar The tumors were also evaluated with five coding mononucleotide repeats [(A)10 in TGFBRII, (A)8 in hMSH3, (G)8 in BAX, (G)8 in IGFIIR, and (C)8 in hMSH6]. The primer sequences and polymerase chain reaction (PCR) conditions for the tetranucleotide repeats, coding mononucleotide repeats, and BAT-26 were as described previously.2Samowitz WS Slattery ML Kerber RA Microsatellite instability in human colonic cancer is not a useful clinical indicator of familial colorectal cancer.Gastroenterology. 1995; 109: 1765-1771Abstract Full Text PDF PubMed Scopus (90) Google Scholar, 6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar, 10Samowitz WS Slattery ML Potter JD Leppert MF BAT-26 and BAT-40 instability in colorectal adenomas and carcinomas and germline polymorphisms.Am J Pathol. 1999; 154: 1637-1641Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar The primer sequences for the remaining four primer sets of the consensus panel were as described previously.11Dietmaier W Wallinger S Bocker T Kullmann F Fishel R Rüschoff J Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression.Cancer Res. 1997; 57: 4749-4756PubMed Google Scholar PCR of these primers consisted of 38 cycles of 20 seconds at 95°C, 20 seconds annealing, and 40 seconds at 72°C, followed by a 10-minute extension at 72°C. The initial annealing temperature was 60°C for BAT-25 and D2S123 and 64°C for D17S250 and D52346. This annealing temperature was decreased 1 degree for each of the next seven cycles and was 52°C for the final 30 cycles. Both tumoral DNA and normal DNA were PCR amplified with the above primer sets. Microsatellite instability for a given primer set was defined as the appearance of one or more new PCR products either smaller or larger than those produced from normal DNA. Results from the tetranucleotide repeat panel were considered to indicate significant microsatellite instability if three or more of the 10 repeats were unstable. Results were considered to indicate stability if <30% of the repeats were unstable and at least six of the 10 repeats were typed. Results from the consensus panel were considered to indicate significant microsatellite instability if two or more of the five repeats were unstable. Results from the consensus panel were considered to indicate stability if no repeats were unstable and at least four were typed or if one of five repeats were unstable. Using these criteria, 92.1% of tumors were successfully classified as unstable or stable by the tetranucleotide repeats and 90.3% were classified by the consensus panel. Microsatellite instability was also assessed using one of the consensus panel repeats, BAT-26, by itself. Instability in this mononucleotide repeat has been reported to be highly correlated with generalized dinucleotide repeat instability.12Hoang J-M Cottu PH Thuille B Salmon RJ Thomas G Hamelin R BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell lines.Cancer Res. 1997; 57: 300-303PubMed Google Scholar Instability in the coding mononucleotide repeats was considered in two ways: instability in any of the five coding repeats, and instability in TGFβRII, the coding repeat most frequently mutated in unstable tumors.6Samowitz WS Slattery ML Regional reproducibility of microsatellite instability in sporadic colorectal cancer.Genes Chromosom Cancer. 1999; 26: 106-114Crossref PubMed Scopus (39) Google Scholar, 13Yamamoto H Sawai H Perucho M Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype.Cancer Res. 1997; 57: 4420-4426PubMed Google Scholar Codons 12 and 13 of the K-ras gene were evaluated for mutations. Exon 1 of K-ras was amplified as described previously14Sidransky D Tokino T Hamilton SR Kinzler KW Levin B Frost P Vogelstein B Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors.Science. 1992; 256: 102-105Crossref PubMed Scopus (687) Google Scholar except that primers were tailed with universal primer (UP) and reverse primer (RP) for sequencing. PCR products were sequenced using prism Big Dye terminators and cycle sequencing with Taq FS DNA polymerase. DNA sequence was collected and analyzed on an ABI prism 377 automated DNA sequencer (Applied Biosystems, Foster City, CA). Automated immunohistochemical staining for p53 was performed using the D07 mouse monoclonal antibody and the percentage of p53-positive tumor cell nuclei was determined as described previously.15Lynch BJ Komaromy-Hiller G Bronstein IB Holden JA Expression of DNA topoisomerase I, DNA topoisomerase II-alpha, and p53 in metastatic malignant melanoma.Hum Pathol. 1998; 29: 1240-1245Abstract Full Text PDF PubMed Scopus (29) Google Scholar This antibody and experimental technique have been shown to be highly specific and predictive for p53 mutations in colon cancer.16Baas IO Mulder JR Offerhaus GJ Vogelstein B Hamilton SR An evaluation of six antibodies for immunohistochemistry of mutant p53 gene product in archival colorectal neoplasms.J Pathol. 1994; 172: 5-12Crossref PubMed Scopus (530) Google Scholar Immunostained slides were evaluated by one of the authors (JAH) without knowledge of the respective clinical parameters or the results of the other analyses in this study. We defined overexpression of p53 as tumors with 50% or more tumor cell nuclei staining positively with the antibody.17Rashid A Zahurak M Goodman SN Hamilton SR Genetic epidemiology of mutated K-ras proto-oncogene, altered suppressor genes, and microsatellite instability in colorectal adenomas.Gut. 1999; 44: 826-833Crossref PubMed Scopus (79) Google Scholar Paraffin blocks for this aspect of the study were available on 274 individuals. Unconditional logistic regression models were fit to estimate the association between microsatellite instability and Ki-ras mutation or p53 overexpression after adjusting for age, sex, and tumor site. In these models, different indicators of microsatellite instability were used to predict a dichotomous dependent variable of wild-type Ki-ras versus mutated Ki-ras or p53-negative (<50% p53 nuclear staining) versus p53 overexpression. These data are reported as the odds ratio and 95% confidence interval for having microsatellite instability but lacking either K-ras mutation or p53 overexpression. Instability results for the panel of 10 tetranucleotide repeats, the consensus panel, Bat 26 by itself, TGFβRII, and instability with any coding mononucleotide repeat are shown in Table 1. Overall instability rates were fairly similar among the various measures, ranging from 10.1 to 13.8%. All measures showed more instability in proximal tumors (19.5 to 23.9%) than distal tumors (1.4 to 4%); these differences were all statistically significant (P < 0.001, chi-square test). A representative example of instability in a tetranucleotide repeat, dinucleotide repeat, noncoding mononucleotide repeat (BAT-26), and a coding mononucleotide repeat (TGFβRII) from the same tumor is shown in Figure 1.Table 1Microsatellite Instability (MI) as Determined by Various Measures of InstabilityInstability measureOverall MIMI in proximal tumorsMI in distal tumorsP value*All P values based on chi-square test comparing the percentage of proximal tumors with microsatellite instability versus the percentage of distal tumors with microsatellite instability.10 tetranucleotides13.8% (63/457)23.9% (54/226)4.0% (8/201)< 0.001Consensus panel12.5% (56/448)22.6% (49/217)2.5% (5/202)< 0.001BAT-2611.4% (53/466)21.2% (47/222)2.3% (5/213)< 0.001TGFβRII10.1% (47/466)19.5% (44/226)1.4% (3/210)< 0.001Any coding mononucleotide11.9% (57/481)21.4% (49/229)3.2% (7/220)< 0.001* All P values based on chi-square test comparing the percentage of proximal tumors with microsatellite instability versus the percentage of distal tumors with microsatellite instability. Open table in a new tab Codon 12 or 13 K-ras gene mutations were identified in 155 of 467 (33.2%) tumors. The type and frequency of ras gene mutations are detailed in Table 2. Ras gene mutations were seen in a higher percentage of proximal (42.5%, 94 of 221) than distal (22.1%, 46 of 208) tumors; this difference was statistically significant (P< 0.001, chi-square test). The relationship between ras gene mutations and microsatellite instability (as determined by the various measures of instability) is summarized in Table 3. All measures of instability showed a higher percentage of ras gene mutations in stable tumors (36 to 38.1%) than in unstable tumors (4.7 to 11.8%); these differences were all statistically significant (P < 0.001, chi-square test). A logistic regression analysis revealed that the inverse association of microsatellite instability with ras gene mutations was independent of tumor site, age, and gender. The strength of the inverse association comparing wild-type K-ras to mutant K-ras for the various indicators of instability was similar with odds ratios ranging from 8.3 to 20.0 (Table 4), and all were statistically significant (P < 0.01).Table 2Type and Frequency of ras Gene MutationsBase pair change*1G and 2G are first two bases of codon 12, 5G is second base of codon 13.Amino acid change†Changed codon (12 or 13) indicated by superscript.Percentage of ras mutations2G to AGly12 to Asp34.85G to AGly13 to Asp23.22G to TGly12 to Val19.41G to TGly12 to Cys10.31G to AGly12 to Ser4.52G to A (H)‡H indicates homozygous mutation.Gly12 to Asp1.32G to C (H)Gly12 to Ala1.32G to T (H)Gly12 to Val1.31G to CGly12 to Arg0.62G to CGly12 to Ala0.61G to A (H)Gly12 to Ser0.61G to T (H)Gly12 to Cys0.65G to A (H)Gly13 to Asp0.61 and 5G to AGly12 to Ser0.6Gly13 to Asp* 1G and 2G are first two bases of codon 12, 5G is second base of codon 13.† Changed codon (12 or 13) indicated by superscript.‡ H indicates homozygous mutation. Open table in a new tab Table 3Comparison of K-ras Gene Mutations with Microsatellite InstabilityInstability measureras Mutations in stable tumorsras Mutations in unstable tumorsP value*All P values based on chi-square test comparing the percentage of stable tumors with ras gene mutations versus the percentage of unstable tumors with ras gene mutations.10 tetranucleotides38.1% (143/375)10.2% (6/59)< 0.001Consensus panel36.4% (136/374)11.8% (6/51)< 0.001BAT-2636.8% (144/391)8.3% (4/48)< 0.001TGFβRII36.0% (143/397)4.7% (2/43)< 0.001Any coding mononucleotide36.2% (145/401)9.8% (5/51)< 0.001* All P values based on chi-square test comparing the percentage of stable tumors with ras gene mutations versus the percentage of unstable tumors with ras gene mutations. Open table in a new tab Table 4Logistic Regression Analyses of Inverse Relationship between Microsatellite Instability and K-ras Mutations and p53 OverexpressionKi-ras OR*OR is odds ratio of the absence of an alteration in K-ras or p53 in tumors with microsatellite instability; CI is confidence interval. (95% CI)p53 OR (95% CI)10 tetranucleotides9.1 (3.4–20.0)2.8 (1.2–6.2)Consensus panel9.1 (3.3–25.0)4.5 (1.8–11.5)Bat-2611.1 (3.7–33.3)8.2 (2.6–25.5)TGFβRII20.0 (4.6–100)9.2 (2.6–33.1)Any coding mononucleotide8.3 (3.1–20)12.9 (3.6–45.5)* OR is odds ratio of the absence of an alteration in K-ras or p53 in tumors with microsatellite instability; CI is confidence interval. Open table in a new tab p53 overexpression was identified in 141 of 274 tumors (51.5%). An example of a tumor with p53 overexpression is shown in Figure 2. p53 overexpression was present in a higher percentage of distal (60.9%, 70 of 115) than proximal (41.0%, 57 of 139) tumors, this difference was statistically significant (P < 0.002, chi-square test). The relationship between p53 overexpression and microsatellite instability (as determined by the various measures of instability) is summarized in Table 5. All measures of instability showed a higher percentage of stable tumors with p53 overexpression (54.3 to 57.2%) than unstable tumors with p53 overexpression (9.1 to 26.3%); these differences were all statistically significant (P < 0.001, chi-square test). A logistic regression analysis revealed that the inverse association of microsatellite instability with p53 overexpression was independent of tumor site, age, and gender. Odds ratios for the inverse association comparing p53 negative (<50% nuclear staining) versus p53 overexpression ranged from 2.8 to 12.9 (Table 4), and all were statistically significant (P < 0.05).Table 5Comparison of p53 Overexpression with Microsatellite InstabilityInstability measurep53 Overexpression in stable tumorsp53 Overexpression in unstable tumorsP value*All P values based on chi-square test comparing the percentage of stable tumors with p53 overexpression versus the percentage of unstable tumors with p53 overexpression.10 tetranucleotides54.3% (120/221)26.3% (10/38)< 0.001Consensus panel55.7% (122/219)20.0% (7/35)< 0.001BAT-2656.5% (130/230)12.1% (4/33)< 0.001TGFβRII55.7% (132/237)11.1% (3/27)< 0.001Any coding mononucleotide57.2% (135/236)9.1% (3/33)< 0.001* All P values based on chi-square test comparing the percentage of stable tumors with p53 overexpression versus the percentage of unstable tumors with p53 overexpression. Open table in a new tab Microsatellite instability in the coding mononucleotide repeats is summarized in Table 6; all observed mutations were frameshifts (addition of one base, deletion of one or two bases). TGFβRII contained the most frequently mutated coding repeat, with length alterations in this poly A repeat in 10.1% (47 of 466) of tumors overall, followed by BAX (6.1%), hMSH3 (5.2%), hMSH6 (2.7%), and IGFIIR (2.3%). As seen in Table 6, all coding mononucleotide repeats were more frequently mutated in unstable (as judged by the Bethesda consensus panel) tumors than stable tumors; these differences were all statistically significant (P < 0.001, chi-square test). At least one coding mononucleotide repeat mutation was seen in 85.7% (48 of 56) of unstable tumors but in only 1.0% (4 of 392) of stable tumors; this difference was also statistically significant (P< 0.001, chi-square test).Table 6Type and Frequency of Coding Mononucleotide Repeat InstabilityCoding mononucleotideChanges in repeat lengthOverall mutation frequencyMutations in unstable tumors*Unstable and stable as defined by the Bethesda consensus panel.Mutations in stable tumors*Unstable and stable as defined by the Bethesda consensus panel.P value†All P values based on chi-square test comparing the percentage of stable tumors with the respective mononucleotide repeat mutation versus the percentage of unstable tumors with that mutation.TGFβRII+1,−1, −210.1% (47/466)74.5% (41/55)0.3% (1/383)< .001BAX+1, −16.1% (23/375)39.6% (19/48)0.3% (1/309)< .001hMSH3+1,−1,−25.2% (21/401)39.6% (19/48)0.0% (0/329)< .001hMSH6+1,−12.7% (13/473)16.4% (9/55)0.5% (2/390)< .001IGFIIR+1, −12.3% (9/396)19.1% (9/47)0.0% (0/327)< .001* Unstable and stable as defined by the Bethesda consensus panel.† All P values based on chi-square test comparing the percentage of stable tumors with the respective mononucleotide repeat mutation versus the percentage of unstable tumors with that mutation. Open table in a new tab Table 7 shows a comparison of the panel of 10 tetranucleotide repeats with the other measures of instability. Microsatellite instability as determined by the 10 tetranucleotide repeats was significantly related to microsatellite instability as determined by the consensus panel, BAT-26, TGFβRII, or instability in any coding mononucleotide repeat (P < 0.001, chi-square test). Table 8 shows a comparison of the consensus panel with BAT-26 by itself. There are very few tumors in which either BAT-26 or the consensus panel alone is unstable, and there is a significant relationship between these two measures of microsatellite instability (P < 0.001, chi-square test).Table 7Comparison of Panel of 10 Tetranucleotide Repeats with other Measure of InstabilityPanel of 10 tetranucleotide repeats*P values are based on chi-square tests comparing microsatellite instability as determined by the panel of 10 tetranucleotide repeats with microsatellite instability determined by the other measures of instability.StableUnstableP valueConsensus panelStable3692Unstable551< 0.001BAT-26Stable3839Unstable449< 0.001TGFβRIIStable38216Unstable344< 0.001Any coding mononucleotideStable38413Unstable849< 0.001* P values are based on chi-square tests comparing microsatellite instability as determined by the panel of 10 tetranucleotide repeats with microsatellite instability determined by the other measures of instability. Open table in a new tab Table 8Comparison of BAT-26 (by Itself) with the Consensus PanelBAT-26Consensus panelStableUnstableP value*P value based on a chi-square test comparing microsatellite instability as determined by BAT-26 by itself versus instability determined by the consensus panel.Stable3851Unstable551<0.001* P value based on a chi-square test comparing microsatellite instability as determined by BAT-26 by itself versus instability determined by the consensus panel. Open table in a new tab This study shows highly statistically significant inverse relationships between microsatellite instability and K-ras gene mutations and p53 overexpression in colon cancers. K-ras mutations were identified in 33.2% of tumors. This is consistent with previous studies that, with rare exceptions,18Kern SE Fearon ER Tersmette KWF Enterline JP Leppert M Nakamura Y White R Vogelstein B Hamilton SR Allelic loss in colorectal carcinoma.JAMA. 1989; 261: 3099-3103Crossref PubMed Scopus (386) Google Scholar have identified K-ras mutations in ∼30 to 40% of colon cancers.19Andreyev HJN Norman AR Cunningham D Oates JR Clarke PA Kirsten ras mutations in patients with colorectal cancer: the multicenter “RASCAL” study.J Natl Cancer Inst. 1998; 90: 675-684Crossref PubMed Scopus (655) Google Scholar, 20Laurent-Puig P Olschwang S Delattre O Remvikos Y Asselain B Melot T Validire P Muleris M Girodet J Salmon RJ Thomas G Survival and acquired genetic alterations in colorectal cancer.Gastroenterology. 1992; 102: 1136-1141PubMed Google Scholar, 21Finkelstein SD Sayegh R Bakker A Swalsky P Determination of tumor aggressiveness in co

The objective of this study was to examine the effects of the intake of dietary fat upon colorectal cancer risk in a combined analysis of data from 13 case-control studies previously conducted in populations with differing colorectal cancer rates and dietary practices. Original data records for 5,287 cases of colorectal cancer and 10,470 controls were combined. Logistic regression analysis was used to estimate odds ratios (OR) for intakes of total energy, total fat and its components, and cholesterol. Positive associations with energy intake were observed for 11 of the 13 studies. However, there was little, if any, evidence of any energy-independent effect of either total fat with ORs of 1.00, 0.95, 1.01, 1.02, and 0.92 for quintiles of residuals of total fat intake (P trend = 0.67) or for saturated fat with ORs of 1.00, 1.08, 1.06, 1.21, and 1.06 (P trend = 0.39). The analysis suggests that, among these case-control studies, there is no energy-independent association between dietary fat intake and risk of colorectal cancer. It also suggests that simple substitution of fat by other sources of calories is unlikely to reduce meaningfully the risk of colorectal cancer.

Physical activity has been inconsistently associated with rectal cancer despite the consistent association between physical activity and colon cancer. In this study, the authors evaluated the association between physical activity and rectal cancer using the same questionnaire used to evaluate the previously reported association with colon cancer. A population-based study of 952 incident cases of cancer in the rectum and rectosigmoid junction and 1,205 age- and sex-matched controls was conducted in Utah and northern California at the Kaiser Permanente Medical Care Program between 1997 and 2002. Vigorous physical activity was associated with reduced risk of rectal cancer in both men and women (odds ratio (OR) = 0.60, 95% confidence interval (CI): 0.44, 0.81 for men; OR = 0.59, 95% CI: 0.40, 0.86 for women). Among men, moderate levels of physical activity also were associated with reduced risk of rectal cancer (OR = 0.70, 95% CI: 0.51, 0.97). Participation in vigorous activity over the past 20 years conferred the greatest protection for both men and women (OR = 0.55, 95% CI: 0.39, 0.78 for men; OR = 0.44, 95% CI: 0.30, 0.67 for women). In summary, physical activity was associated with reduced risk of rectal cancer in these data. The reduced risk was similar to that previously observed for colon cancer.

<h3>Objective.</h3> —The purpose of this study is to assess the impact of family history on the risk of developing breast cancer. <h3>Design.</h3> —A case-control study design was used. <h3>Setting.</h3> —To provide a comprehensive assessment of family history risk, we used the Utah Population Database, a linked database compiled of genealogy data of the descendants of Mormon pioneer families, cancer data from the Utah Cancer Registry, and mortality data from the Utah Department of Vital Statistics. <h3>Patients.</h3> —All women diagnosed with breast cancer who were in the genealogy database and the Utah Cancer Registry were included. Controls were women selected from the genealogy, who like cases had no record of previous cancer. They were matched to the cases by age and place of birth. <h3>Outcome.</h3> —Several definitions of family history were used. The total familial risk variable, developed to work effectively in the Utah Genealogy Database, accounts for all family members, their degree of relatedness to the case, and the amount of time they were observed for possible cancer diagnosis. <h3>Results.</h3> —A threefold increase in risk, estimated by the odds ratio (OR), of breast cancer among those with the highest family history score (6% of cases) was observed when compared with those with the lowest family history score. The OR for women with a first-degree relative with breast cancer was 2.45 (95% confidence interval [Cl], 1.84 to 3.06). If the nearest relative was a second-degree relative, the OR was 1.82 (95% Cl, 1.39 to 2.24); if the nearest relative was a third-degree relative, the OR was 1.35 (95% Cl, 1.07 to 1.64). A slightly greater risk was observed if the first-degree relative was a woman's mother (OR, 2.44; 95% Cl, 1.77 to 3.42) rather than a sister (OR, 2.01; 95% Cl, 1.66 to 2.43). Among subjects diagnosed before the age of 50 years, the disease experience of relatives prior to age 50 was most important, while for older subjects the experience of relatives of all ages was of roughly equal importance. Women who developed contralateral breast cancer within 3 years of initial diagnosis were nearly 10 times as likely as women without breast cancer to have a first-degree relative with breast cancer. Based on the risk estimates in this study, we have estimated that approximately 17% to 19% of breast cancer in the population could be attributed to family history. Women who had a first-degree relative with colon cancer had a 30% increased risk of breast cancer. <h3>Conclusions.</h3> —In this study population, women with a family history of breast cancer, even if the nearest relative with breast cancer is a third-degree relative, are at increased risk of the disease. (<i>JAMA</i>. 1993;270:1563-1568)

Abstract It has been proposed that dietary factors such as folate, alcohol and methionine may be associated with colon cancer because of their involvement in DNA methylation processes. Data from a large population‐based case‐control study of incident colon cancer were used to evaluate whether intake of dietary, obesity, physical activity and nonsteroidal antiinflammatory drugs are associated with a CpG island methylator phenotype (CIMP). The BRAF V600E mutation and 5 CpG island markers (MINT1, MINT2, MINT31, p16 and hMLH1 ) were assessed in 1154 cases of colon cancer. We hypothesized that dietary factors involved in DNA methylation, cruciferous vegetables and use of aspirin/NSAIDs would be associated with CIMP‐high tumors. Dietary folate, vitamins B 6 and B 12 , methionine and alcohol were not associated with increased likelihood of colon tumors with the CIMP‐high (2 or more markers methylated) phenotype. Dietary fiber, physical activity and aspirin and other nonsteroidal antiinflammatory drugs were inversely associated with both CIMP‐low and CIMP‐high tumors. Our results also suggested non‐CIMP pathways as well. Obese individuals were at 2‐fold increased risk of having a CIMP‐low tumor. Alcohol was associated with an increased risk of tumors that were MSI+ and CIMP‐low. In the presence of smoking 20 or more cigarettes per day, use of NSAIDs did not protect against a BRAF mutation. Our data suggest multiple pathways to colon cancer. They do not support a unique role for dietary folate, alcohol, vitamins B 6 and B 12 and methionine in a CpG island methylator phenotype. © 2006 Wiley‐Liss, Inc.

An attenuated form of familial adenomatous polyposis has been described, but the phenotype remains poorly understood.We performed genetic testing on 810 individuals from 2 attenuated familial adenomatous polyposis kindreds harboring an identical germline adenomatous polyposis coli gene mutation. Colonoscopy was performed on mutation-positive persons. The disease-causing mutation was present in 184 individuals. Adenomatous polyps were present in 111 of 120 gene carriers who had colonoscopy at an average age of 41 years. The median number of adenomas was 25 (range, 0–470), with striking variability of polyp numbers and a proximal colonic predominance of polyps. Colorectal cancer occurred in 27 mutation carriers (average age, 58 years; range, 29–81 years), with 75% in the proximal colon. The cumulative risk of colorectal cancer by age 80 was estimated to be 69%. An average of 3.4 recurrent polyps (range, 0–29) were found in the postcolectomy rectal remnant over a mean of 7.8 years (range, 1–34 years), with 1 rectal cancer. This investigation shows that attenuated familial adenomatous polyposis in the kindreds examined shows a much smaller median number of polyps than typical familial adenomatous polyposis, a wide variability in polyp number even at older ages, and a more proximal colonic location of polyps and cancer, yet it is associated with an extremely high risk of colon cancer. The phenotype of attenuated familial adenomatous polyposis mimics typical familial adenomatous polyposis in some cases but in others is difficult to distinguish from sporadic adenomas and colorectal cancer, thus making genetic testing particularly important.

This study evaluated the reliability and comparative validity of the dietary history survey method developed for CARDIA, a longitudinal investigation of life-styles and the evolution of cardiovascular risk factors in young adults. The method was tested in a sample of 30 white men, 33 white women, 33 black men, and 32 black women, aged 18 to 35 years, in four regions reflecting the race, sex, age, and geographical distribution of CARDIA participants. For 64 of the participants, two dietary history interviews, 1 month apart, were conducted by trained nutritionists. These data were used to examine the reliability of the method. For all participants, seven telephone- assessed 24-hour dietary recalls were randomly scheduled during a 28-day period and were followed by a dietary history interview. These data were used to examine the comparative validity of the method. Calories, total fat, saturated fat, polyunsaturated fat, monounsaturated fat, dietary cholesterol, protein, carbohydrate, alcohol, potassium, calcium, and vitamin A were selected by the CARDIA Nutrition Working Group as the nutrients for comparison. Mean nutrient values from the first history tended to be higher than those obtained from the last history. However, for a majority of the nutrients, the differences were significant for blacks but not for whites. The correlations for the log-transformed nutrient values and calorie-adjusted nutrient values from the two histories were generally in the range of 0.50 to 0.80 for whites. For blacks, the correlations were lower, with a majority in the range of 0.30 to 0.70. The average nutrient values estimated from the histories were higher than those estimated from the average of the seven 24-hour recalls. The differences in blacks were larger than in whites. For both the log-transformed nutrient values and the calorie-adjusted nutrient values, the correlations between the two methods were generally larger than 0.50 for whites. However, for blacks, the correlations were lower, and for several macronutrients, the correlations were close to zero. These results suggest that the CARDIA dietary history is a reasonably reliable and valid dietary survey method for obtaining information about habitual intakes in whites. In blacks, the results are less consistent. The black-white differences remained when the analyses were stratified by education. These results raise a question about differences in reporting between blacks and whites.

Purpose To determine the association of dietary patterns with cancer recurrence and mortality of early-stage breast cancer survivors. Patients and Methods Patients included 1,901 Life After Cancer Epidemiology Study participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited primarily from the Kaiser Permanente Northern California Cancer Registry. Diet was assessed at cohort entry using a food frequency questionnaire. Two dietary patterns were identified: prudent (high intakes of fruits, vegetables, whole grains, and poultry) and Western (high intakes of red and processed meats and refined grains). Two hundred sixty-eight breast cancer recurrences and 226 all-cause deaths (128 attributable to breast cancer) were ascertained. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% CIs. Results Increasing adherence to a prudent dietary pattern was associated with a statistically significant decreasing risk of overall death (P trend = .02; HR for highest quartile = 0.57; 95% CI, 0.36 to 0.90) and death from non–breast cancer causes (P trend = .003; HR for highest quartile = 0.35; 95% CI, 0.17 to 0.73). In contrast, increasing consumption of a Western dietary pattern was related to an increasing risk of overall death (P trend = .05) and death from non–breast cancer causes (P = .02). Neither dietary pattern was associated with risk of breast cancer recurrence or death from breast cancer. These observations were generally not modified by physical activity, being overweight, or smoking. Conclusion Women diagnosed with early-stage breast cancer might improve overall prognosis and survival by adopting more healthful dietary patterns.

Levels and changes in self-reported physical activity over a 7-year period were examined to determine tracking and to estimate the proportion of total cohort change attributable to secular trends. A population-based sample of 2,328 men and 2,787 women aged 18-30 years at baseline (52% black and 48% white) from Birmingham, Alabama, Chicago, Illinois, Minneapolis, Minnesota, and Oakland, California, were examined four times between 1985-1986 and 1992-1993. The intraclass correlation for up to four measures was 0.57 for the entire sample, varying between 0.57 for white men and 0.42 for black women, indicating a moderate tendency for tracking. The energy expenditure in physical activity at each examination was greatest in black men and, compared with black men, about 5% less in white men, 30% less in white women, and 50% less in black women. The total cohort decrease in mean physical activity was approximately 30% in each race-sex group. The secular trend accounted for 38% of the total cohort change in black men, 43% in black women, 52% in white men, and 81% in white women. Physical activity declined sharply during the early years of adulthood, partly because of secular trend. Young adults are therefore an important target group for physical activity promotion programs to reverse individual and populationwide declines prior to middle age.

Abstract The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is involved in immune function and cell growth. We evaluated the association between genetic variation in JAK1 (10 SNPs), JAK2 (9 SNPs), TYK2 (5 SNPs), suppressors of cytokine signaling ( SOCS ) 1 (2 SNPs), SOCS2 (2 SNPs), STAT1 (16 SNPs), STAT2 (2 SNPs), STAT3 (6 SNPs), STAT4 (21 SNPs), STAT5A (2 SNPs), STAT5B (3 SNPs), STAT6 (4 SNPs) with risk of colorectal cancer. We used data from population‐based case‐control studies (colon cancer n = 1555 cases, 1,956 controls; rectal cancer n = 754 cases, 959 controls). JAK2 , SOCS2 , STAT1 , STAT3 , STAT5A , STAT5B , and STAT6 were associated with colon cancer; STAT3 , STAT4 , STAT6 , and TYK2 were associated with rectal cancer. Given the biological role of the JAK/STAT‐signaling pathway and cytokines, we evaluated interaction with IFNG, TNF, and IL6; numerous statistically significant associations after adjustment for multiple comparisons were observed. The following statistically significant interactions were observed: TYK2 with aspirin/NSAID use; STAT1 , STAT4 , and TYK2 with estrogen status; and JAK2 , STAT2 , STAT4 , STAT5A , STAT5B , and STAT6 with smoking status and colon cancer risk; JAK2 , STAT6 , and TYK2 with aspirin/NSAID use; JAK1 with estrogen status; STAT2 with cigarette smoking and rectal cancer. JAK2 , SOCS1 , STAT3 , STAT5 , and TYK2 were associated with colon cancer survival (hazard rate ratio (HRR) of 3.3 95% CI 2.01,5.42 for high mutational load). JAK2 , SOCS1 , STAT1 , STAT4 , and TYK2 were associated with rectal cancer survival (HRR 2.80 95% CI 1.63,4.80). These data support the importance of the JAK/STAT‐signaling pathway in colorectal cancer and suggest targets for intervention. © 2011 Wiley Periodicals, Inc.

The relation between physical fitness and cardiovascular disease mortality was examined in US railroad workers, as a part of the Seven Countries Study. A cohort of 3,043 white, middle-aged men initially aged 22–79 years were first examined in 1957–1960 and re-examined in 1962–1964. Men with clinically diagnosed cardiovascular disease (n = 465) were excluded from this study. This cohort was followed until death or 1977. Mortality was monitored through the Railroad Retirement Board. Physical fitness was ascertained by a sub-maximal treadmill test administered in a Pullman Car converted to a survey laboratory. Exercise heart rate was directly and significantly related to coronary heart disease mortality, cardiovascular disease mortality, and all-cause mortality after adjusting for age. These relations were greatly attenuated when adjusted for blood pressure level. The risk for coronary heart disease when an exercise test heart rate of 135 beats per minute was compared with a rate of 105 beats per minute was 1.43, after adjusting for age, and 1.20, after adjusting for blood pressure, serum cholesterol levels, and smoking, as well as age. Results from this study suggest that middle-aged men with lower levels of physical fitness, as shown by higher sub-maximal exercise test heart rates, are at greater risk of dying of coronary heart disease, cardiovascular disease, and all causes in an average follow-up of 20 years. This greater risk is largely due to higher blood pressure levels.

Response rates are an important component of epidemiologic research. The purposes of this study are (a) to evaluate how response rates are defined and calculated for control subjects in epidemiologic case-control studies, and (b) to explore factors that may impact response in epidemiologic studies. Our results show that the method of control subject selection has an impact on study response. Gender of respondent does not appear to impact response rates. However, response rates are generally worse for individuals less than 45 years old. Methods used to calculate response have a great impact on "response rate"; therefore, it is important for researchers to define exactly what the reported response rates represent and how they are derived so that data can be interpreted appropriately.

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when <60 years of age (OR = 0.62, 95% CI = 0.42-0.93). Examination of calcium in conjunction with VDR genotype showed that a significant 40% reduction in risk of rectal cancer was observed for the SS or BB VDR genotypes when calcium intake was low (p interaction = 0.01 for calcium interaction). For colon cancer, high levels of dietary intake of calcium, vitamin D, and low-fat dairy products reduced risk of cancer for the SS or BB VDR genotypes, although the p for interaction was not statistically significant. These data support previous observations that high levels of calcium and vitamin D reduce risk of rectal cancer and provide support for a weak protective effect for the SS and BB VDR genotypes. The risk associated with VDR genotype seems to depend upon the level of dietary calcium and vitamin D and tumor site.

Personal cigarette smoking and exposure to passive smoke as risk factors for cervical cancer were examined in a population-based, case-control study conducted in Utah. Personal cigarette smoking was found to increase the risk of cervical cancer, after adjusting for age, educational level, church attendance, and sexual activity. The adjusted risk estimate associated with being a current smoker was 3.42 (95% confidence interval [Cl], 2.10 to 5.57); for having smoked for 5 or more pack-years, it was 2.81 (95% Cl, 1.73 to 4.55); and for having smoked at least 100 lifetime cigarettes, it was 2.21 (95% Cl, 1.44 to 3.39). The adjusted risk estimate (also adjusted for actual cigarettes smoked) associated with passive smoke exposure for 3 or more hours per day was 2.96 (95% Cl, 1.25 to 7.03). Risk from passive smoking was greater in women who were not smokers (odds ratio, 3.43; 95% Cl, 1.23 to 9.54) than in women who smoked (odds ratio, 2.59; 95% Cl, 0.23 to 29.24).

Journal Article Objective System for Interviewer Performance Evaluation for Use in Epidemiologic Studies Get access Sandra Edwards, Sandra Edwards 1Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Reprint requests to Sandra Edwards, Department of Family and Preventive Medicine, University of Utah School of Medicine, 50 N. Medical Drive, Salt Lake City, UT 84132 Search for other works by this author on: Oxford Academic PubMed Google Scholar Martha L. Slattery, Martha L. Slattery 1Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar Motomi Mori, Motomi Mori 1Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar T. Dennis Berry, T. Dennis Berry 1Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar Bette J. Caan, Bette J. Caan 2Kaiser Permanente Medical Care ProgramOakland, CA Search for other works by this author on: Oxford Academic PubMed Google Scholar Pat Palmer, Pat Palmer 1Department of Family and Preventive Medicine, University of Utah School of MedicineSalt Lake City, UT Search for other works by this author on: Oxford Academic PubMed Google Scholar John D. Potter John D. Potter 3Division of Epidemiology, School of Public Health, University of MinnesotaMinneapolis, MN Search for other works by this author on: Oxford Academic PubMed Google Scholar American Journal of Epidemiology, Volume 140, Issue 11, 1 December 1994, Pages 1020–1028, https://doi.org/10.1093/oxfordjournals.aje.a117192 Published: 01 December 1994 Article history Received: 21 March 1994 Revision received: 26 July 1994 Published: 01 December 1994

Genome-wide association studies (GWAS) have identified more than a dozen loci associated with colorectal cancer (CRC) risk. Here, we examined potential effect-modification between single-nucleotide polymorphisms (SNP) at 10 of these loci and probable or established environmental risk factors for CRC in 7,016 CRC cases and 9,723 controls from nine cohort and case-control studies. We used meta-analysis of an efficient empirical-Bayes estimator to detect potential multiplicative interactions between each of the SNPs [rs16892766 at 8q23.3 (EIF3H/UTP23), rs6983267 at 8q24 (MYC), rs10795668 at 10p14 (FLJ3802842), rs3802842 at 11q23 (LOC120376), rs4444235 at 14q22.2 (BMP4), rs4779584 at 15q13 (GREM1), rs9929218 at 16q22.1 (CDH1), rs4939827 at 18q21 (SMAD7), rs10411210 at 19q13.1 (RHPN2), and rs961253 at 20p12.3 (BMP2)] and select major CRC risk factors (sex, body mass index, height, smoking status, aspirin/nonsteroidal anti-inflammatory drug use, alcohol use, and dietary intake of calcium, folate, red meat, processed meat, vegetables, fruit, and fiber). The strongest statistical evidence for a gene-environment interaction across studies was for vegetable consumption and rs16892766, located on chromosome 8q23.3, near the EIF3H and UTP23 genes (nominal P(interaction) = 1.3 × 10(-4); adjusted P = 0.02). The magnitude of the main effect of the SNP increased with increasing levels of vegetable consumption. No other interactions were statistically significant after adjusting for multiple comparisons. Overall, the association of most CRC susceptibility loci identified in initial GWAS seems to be invariant to the other risk factors considered; however, our results suggest potential modification of the rs16892766 effect by vegetable consumption.

There is a lower incidence of breast cancer among Hispanic women than among non-Hispanic white women. Little is known about the role of diet in this difference.We examined the associations of dietary patterns (Western, Prudent, Native Mexican, Mediterranean, and Dieter) with risk for breast cancer in Hispanic women (757 cases, 867 controls) and non-Hispanic white women (1524 cases, 1598 controls) from the Four-Corners Breast Cancer Study.Dietary intake, physical activity, and other exposures were assessed by using interviews. Dietary patterns were defined via factor analysis. Risk was assessed by using logistic regression with adjustment for age, center, education, smoking, total activity, calories, dietary fiber, dietary calcium, height, parity, recent hormone exposure, family history of breast cancer, menopausal status, and body mass index x recent hormone exposure.The Western (odds ratio for highest versus lowest quartile: 1.32; 95% CI: 1.04, 168; P for trend < 0.01) and Prudent (1.42; 1.14, 1.77; P for trend < 0.01) dietary patterns were associated with greater risk, and the Native Mexican (0.68; 0.55, 0.85; P for trend < 0.01) and Mediterranean (0.76; 0.63, 0.92; P for trend < 0.01) dietary patterns were associated with lower risk of breast cancer. Body mass index modified the associations of the Western diet and breast cancer among postmenopausal women and those of the Native Mexican diet among premenopausal women.Associations of dietary patterns with breast cancer risk varied by menopausal and body mass index status, but there was little difference in associations between non-Hispanic white and Hispanic women.

A population-based case-control study was conducted in Utah to test the hypothesis that calcium decreases the risk of developing colon cancer. A total of 231 cases and 391 controls were identified and interviewed between 1979 and 1982. A quantitative food frequency instrument was used to ascertain individual dietary intake two years prior to diagnosis for the cases and two years prior to interview for the controls. Calcium, calcium per 1,000 calories, and total dairy product consumption were used as indicators of dietary calcium intake. Categories of dietary intake were determined by the distribution of these variables in the control population. A protective effect was observed for males for intake of calcium (odds ratio (OR) = 0.48), calcium per 1,000 calories (OR = 0.35), and total diary products (OR = 0.49). The magnitude of the protective effect from calcium intake increased after adjusting for intake of calories (OR = 0.41), protein (OR = 0.31), and fat (OR = 0.46). Calcium provided less of a protective effect in females, with the odds ratio for calcium being 0.50, 0.55, and 0.56 after adjusting for calories, protein, and fat, respectively. Risk associated with calories, protein, and fat also increased after adjusting for calcium. Of interest is an odds ratio of 5.30 in males for protein after adjusting for calcium. A biologic mechanism is presented to help explain the role of calcium in the development of colon cancer.

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

Abstract Relationships between adenomatous polyposis coli (APC) mutations, BRAF V600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored. In addition, controversies exist about the proportion of tumors with APC mutations in the mutation cluster region (MCR); how commonly APC, Ki-ras, and p53 mutations occur in the same tumor; and whether APC mutations occur in sporadic microsatellite-unstable tumors. The APC gene was therefore sequenced in 90 colonic adenocarcinomas previously evaluated for CIMP, microsatellite instability, BRAF, Ki-ras, and p53. APC mutations were inversely related to BRAF mutations (P = 0.0003) and CIMP (P = 0.02) and directly related to p53 and Ki-ras mutations (P = 0.04). Slightly more than half of APC mutations occurred outside of the MCR, and frameshift mutations were more likely than nonsense mutations to occur in the MCR (21 of 28 versus 12 of 40, P = 0.0003). APC mutations were found in sporadic microsatellite-unstable tumors and were more likely to be frameshifts in short nucleotide repeats (P = 0.007). The occurrence of APC, Ki-ras, and p53 mutations together in the same tumor was uncommon (11.1%). In conclusion, an analysis restricted to the MCR will miss more than half of APC mutations as well as mischaracterize their mutational spectrum. The conventional wisdom that most colon cancers contain APC, Ki-ras, and p53 mutations is incorrect. Microsatellite instability may precede acquisition of APC mutations in sporadic microsatellite-unstable tumors. The relationships of APC mutations to other genetic and epigenetic alterations add to the already impressive genetic heterogeneity of colon cancer. (Mol Cancer Res 2007;5(2):165–70)

To examine whether weight gain after diagnosis of breast cancer affects the risk of breast cancer recurrence.Patients included 3215 women diagnosed with early stage breast cancer (Stage I >1 cm., II, and IIIA) who were enrolled either in an observational cohort of breast cancer survivors or were part of the comparison group of a dietary intervention trial to prevent breast cancer recurrence. We computed weight change from 1 year prior to diagnosis to study enrollment. Delayed entry Cox proportional hazards models were used to evaluate associations of categories of weight change with time to recurrence, controlling for known prognostic factors.Neither moderate (5-10%) nor large (> 10%) weight gain (HR 0.8, 95% CI, 0.6-1.1; HR 0.9, 95% CI, 0.7-1.2, respectively) after breast cancer diagnosis was associated with an increased risk of breast cancer recurrence in the early years post-diagnosis (median time of 73.7 months from diagnosis).Our research provides evidence that weight gain commonly seen in the first several years following a breast cancer diagnosis does not increase a woman's risk for breast cancer recurrence in the first 5-7 years post-diagnosis. However, this research does not address the effects of weight gain on overall survival or on the risk of other new cancers, other prognostic outcomes of concern to the breast cancer survivor.

It is unknown whether dietary patterns or macronutrient composition contribute to the observed differences in rates of overweight and obesity among Hispanic and non-Hispanic white women in the United States. We assessed the association of dietary patterns and macronutrient composition with overweight and obesity in Hispanic and non-Hispanic white women.Cross-sectional analysis of dietary data from a case-control study of breast cancer.Population-based control participants (871 Hispanic and 1,599 non-Hispanic white women) from the southwestern United States who completed the diet and other components of the interview and whose anthropometric measurements were available.Body mass index (BMI; calculated as kg/m(2)), weight status (overweight, BMI 25 to 29.9; obese, BMI>30).Dietary patterns were defined using factor analysis. Associations of dietary patterns and macronutrient composition with overweight and obesity as compared with normal weight were assessed with logistic regression.Hispanic women reported consuming more energy, a greater proportion of energy from fat and vegetable protein, less alcohol, and less energy from animal protein compared with non-Hispanic white women. Western and dieter patterns were associated with higher prevalence of overweight and obesity; the Prudent dietary pattern was associated with a 29% lower prevalence of overweight and a halving of the prevalence of obesity similarly in Hispanic and non-Hispanic white women. Higher proportions of energy from protein (odds ratio [OR] 1.81, 95% confidence interval [CI] 1.28 to 2.56) and animal protein (OR 2.10 95% CI 1.47 to 2.98) were associated with a greater risk of overweight; greater proportions of energy from fat (OR 2.28, 95% CI 1.27 to 4.08), protein (3.55 95% CI 2.38 to 5.29), or animal protein (3.44 95% CI 2.31 to 5.14) were associated with higher risk of obesity among non-Hispanic white women only.A Western dietary pattern was associated with greater risk and a Prudent diet with reduced risk of overweight and obesity. To reduce risk of overweight and obesity, Hispanic women should maintain healthful aspects of a native Hispanic diet, and non-Hispanic white women should replace animal protein with vegetable protein.

Risk for colorectal cancer (CRC) can be greatly reduced through screening. To aid in the development of screening strategies, we refined models designed to determine risk of CRC by incorporating information from common genetic susceptibility loci.By using data collected from more than 12,000 participants in 6 studies performed from 1990 through 2011 in the United States and Germany, we developed risk determination models based on sex, age, family history, genetic risk score (number of risk alleles carried at 27 validated common CRC susceptibility loci), and history of endoscopic examinations. The model was validated using data collected from approximately 1800 participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, conducted from 1993 through 2001 in the United States.We identified a CRC genetic risk score that independently predicted which patients in the training set would develop CRC. Compared with determination of risk based only on family history, adding the genetic risk score increased the discriminatory accuracy from 0.51 to 0.59 (P = .0028) for men and from 0.52 to 0.56 (P = .14) for women. We calculated age- and sex-specific 10-year CRC absolute risk estimates based on the number of risk alleles, family history, and history of endoscopic examinations. A model that included a genetic risk score better determined the recommended starting age for screening in subjects with and without family histories of CRC. The starting age for high-risk men (family history of CRC and genetic risk score, 90%) was 42 years, and for low-risk men (no family history of CRC and genetic risk score, 10%) was 52 years. For men with no family history and a high genetic risk score (90%), the starting age would be 47 years; this is an intermediate value that is 5 years earlier than it would be for men with a genetic risk score of 10%. Similar trends were observed in women.By incorporating information on CRC risk alleles, we created a model to determine the risk for CRC more accurately. This model might be used to develop screening and prevention strategies.

MicroRNAs are thought to have an impact on cell proliferation, apoptosis, stress responses, maintenance of stem cell potency, and metabolism and are, therefore, important in the carcinogenic process. In this study, we examined 40 colon tumors, 30 rectal tumors, and 30 normal tissue samples (10 proximal colon, 10 distal colon, and 10 rectal paired with cancer cases) to examine miRNA expression profiles in colon and rectal tumors. MiRNA expression levels were adjusted for multiple comparisons; tumor tissue was compared with noncancerous tissue from the same site. A comparison of normal tissue showed 287 unique miRNAs that were significantly differentially expressed at the 1.5-fold level and 73 with over a two-fold difference in expression between colon and rectal tissue. Examination of miRNAs that were significantly differentially expressed at the 1.5-fold level by tumor phenotype showed 143 unique miRNAs differentially expression for microsatellite instability positive (MSI+) colon tumors; 129 unique miRNAs differentially expressed for CpG Island Methylator Phenotype positive (CIMP+) colon tumors; 135 miRNAs were differentially expressed for KRAS2-mutated colon tumors, and 139 miRNAs were differentially expressed for TP53-mutated colon tumors. Similar numbers of differentially expressed miRNAs were observed for rectal tumors, although the miRNAs differentially expressed differed. There were 129 unique miRNAs for CIMP+, 143 unique miRNAs for KRAS2-mutated, and 136 unique miRNAs for TP53-mutated rectal tumors. These results suggest the importance of miRNAs in colorectal cancer and the need for studies that can confirm these results and provide insight into the diet, lifestyle, and genetic factors that influence miRNA expression.

The long-term prognostic role of functional limitations among women with breast cancer is poorly understood.We studied a cohort of 2202 women with breast cancer at two sites in the United States, who provided complete information on body functions involving endurance, strength, muscular range of motion, and small muscle dexterity following initial adjuvant treatment. Associations of baseline functional limitations with survival were evaluated in delayed entry Cox proportional hazards models, with adjustment for baseline sociodemographic factors, body mass index, smoking, physical activity, comorbidity, tumor characteristics, and treatment. Difference in covariates between women with and without limitations was assessed with Pearson χ(2) and Student t tests. All statistical tests were two-sided.During the median follow-up of 9 years, 112 deaths were attributable to competing causes (5% of the cohort) and 157 were attributable to breast cancer causes (7% of the cohort). At least one functional limitation was present in 39% of study participants. Proportionately, more breast cancer patients with functional limitations after initial adjuvant treatment were older, less educated, and obese (P < .001). In multivariable models, functional limitations were associated with a statistically significantly increased risk of death from all causes (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.03 to 1.92) and from competing causes (HR = 2.60, 95% CI = 1.69 to 3.98) but not from breast cancer (HR = 0.90, 95% CI = 0.64 to 1.26). The relationship between functional limitations and overall survival differed by tumor stage (among women with stage I and stage III breast cancer, HR = 2.02, 95% CI = 1.23 to 3.32 and HR = 0.74, 95% CI = 0.42 to 1.30, respectively).In this prospective cohort study, functional limitations following initial breast cancer treatment were associated with an important reduction in all-cause and competing-cause survival, irrespective of clinical, lifestyle, and sociodemographic factors.

MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population‐based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa‐miR‐145‐5p and hsa‐miR‐31‐5p showed increased expression with more advanced tumor stage, while hsa‐miR‐200b‐3p, hsa‐miR‐215 and hsa‐miR‐451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa‐miR‐145‐3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa‐miR‐9‐3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa‐miR‐335‐5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa‐miR‐374a‐5p, hsa‐miR‐570‐3p and hsa‐miR‐18a‐5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site.

PURPOSE: Differences in acquired mutations in colon and rectal tumors may account for differences in risk factors. In this study, we examined similarities and differences in somatic alterations in colon and rectal tumors. METHODS: Cases were identified from two large population-based case-control studies of colon cancer and rectal cancer. We sequenced Exons 5 to 8 of the p53 gene and Codons 12 and 13 of the Ki-ras gene to identify tumor mutations. Microsatellite instability was determined based on BAT26 and TGFβRII analysis; CpG island methylator phenotype was determined based on having two or more of the following markers methylated p16, MLH1, MINT1, MINT2, and MINT31. RESULTS: p53 mutations were observed in 39.7% of proximal, 51.0% of distal, and 46.6% of rectal tumors; Ki-ras mutations were observed in 36.0% of proximal, 26.9% of distal, and 30.5% of rectal tumors. Although 40.9% of proximal tumors were considered CpG island methylator phenotype positive (having two or more of five markers methylated), only 12.9% of distal and 11.9% of rectal tumors were CpG island methylator phenotype positive. Likewise, microsatellite instability was observed in 23.7% of proximal and only 3.8% of distal and 2.0% of rectal tumors. More than 50% of distal colon or rectal tumors had only one acquired mutation, whereas only 35.1% of proximal tumors had one mutation. The most common single mutation for colon and rectal tumors was p53 followed by Ki-ras mutations. CONCLUSIONS: Our findings suggest that unique mutational pathways are involved in the development of most colorectal tumors. Proximal colon cancers are more likely than rectal and distal colon tumors to have microsatellite instability, CpG island methylator phenotype, and Ki-ras mutations, whereas rectal and distal colon tumors are more likely than proximal colon tumors to have a p53 mutation. Overall, rectal and distal colon tumors share similar mutational frequencies which are different from those observed in proximal colon tumors.

A sizable fraction of colorectal cancer (CRC) is expected to be explained by heritable factors, with heritability estimates ranging from 12 to 35% twin and family studies. Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) associated with CRC risk. Although it has been shown that these CRC susceptibility SNPs only explain a small proportion of the genetic risk, it is not clear how much of the heritability these SNPs explain and how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we estimated the heritability of CRC under different scenarios using Genome-Wide Complex Trait Analysis in the Genetics and Epidemiology of Colorectal Cancer Consortium including 8025 cases and 10 814 controls. We estimated that the heritability explained by known common CRC SNPs identified in GWAS was 0.65% (95% CI:0.3-1%; P = 1.11 × 10-16), whereas the heritability explained by all common SNPs was at least 7.42% (95% CI: 4.71-10.12%; P = 8.13 × 10(-8)), suggesting that many common variants associated with CRC risk remain to be detected. Comparing the heritability explained by the common variants with that from twin and family studies, a fraction of the heritability may be explained by other genetic variants, such as rare variants. In addition, our analysis showed that the gene × smoking interaction explained a significant proportion of the CRC variance (P = 1.26 × 10(-2)). In summary, our results suggest that known CRC SNPs only explain a small proportion of the heritability and more common SNPs have yet to be identified.

Background & AimsKnown genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC.MethodsThis discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases.ResultsWe identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10−8 to 1.24 × 10−12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%–18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2.ConclusionsWe identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis. Known genetic factors explain only a small fraction of genetic variation in colorectal cancer (CRC). We conducted a genome-wide association study to identify risk loci for CRC. This discovery stage included 8027 cases and 22,577 controls of East-Asian ancestry. Promising variants were evaluated in studies including as many as 11,044 cases and 12,047 controls. Tumor-adjacent normal tissues from 188 patients were analyzed to evaluate correlations of risk variants with expression levels of nearby genes. Potential functionality of risk variants were evaluated using public genomic and epigenomic databases. We identified 4 loci associated with CRC risk; P values for the most significant variant in each locus ranged from 3.92 × 10−8 to 1.24 × 10−12: 6p21.1 (rs4711689), 8q23.3 (rs2450115, rs6469656), 10q24.3 (rs4919687), and 12p13.3 (rs11064437). We also identified 2 risk variants at loci previously associated with CRC: 10q25.2 (rs10506868) and 20q13.3 (rs6061231). These risk variants, conferring an approximate 10%–18% increase in risk per allele, are located either inside or near protein-coding genes that include transcription factor EB (lysosome biogenesis and autophagy), eukaryotic translation initiation factor 3, subunit H (initiation of translation), cytochrome P450, family 17, subfamily A, polypeptide 1 (steroidogenesis), splA/ryanodine receptor domain and SOCS box containing 2 (proteasome degradation), and ribosomal protein S2 (ribosome biogenesis). Gene expression analyses showed a significant association (P < .05) for rs4711689 with transcription factor EB, rs6469656 with eukaryotic translation initiation factor 3, subunit H, rs11064437 with splA/ryanodine receptor domain and SOCS box containing 2, and rs6061231 with ribosomal protein S2. We identified susceptibility loci and genes associated with CRC risk, linking CRC predisposition to steroid hormone, protein synthesis and degradation, and autophagy pathways and providing added insight into the mechanism of CRC pathogenesis.

MiRNAs are small, non-protein-coding RNA molecules that regulate gene expression either by post-transcriptionally suppressing mRNA translation or by mRNA degradation. We examine differentially expressed miRNAs in colorectal carcinomas, adenomas and normal colonic mucosa. Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. A total of 1893 carcinoma/normal-paired samples and 290 adenoma tissue samples were run on the Agilent Human miRNA Microarray V19.0 which contained 2006 miRNAs. We tested for significant differences in miRNA expression between paired carcinoma/adenoma/normal colonic tissue samples. Fewer than 600 miRNAs were expressed in >80% of people for colonic tissue; of these 86.5% were statistically differentially expressed between carcinoma and normal colonic mucosa using a false discovery rate of 0.05. Roughly half of these differentially expressed miRNAs showed a progression in levels of expression from normal to adenoma to carcinoma tissue. Other miRNAs appeared to be altered at the normal to adenoma stage, while others were only altered at the adenoma to carcinoma stage or only at the normal to carcinoma stage. Evaluation of the Agilent platform showed a high degree of repeatability ( r = 0.98) and reasonable agreement with the NanoString platform. Our data suggest that miRNAs are highly dysregulated in colorectal tissue among individuals with colorectal cancer; the pattern of disruption varies by miRNA as tissue progresses from normal to adenoma to carcinoma.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

Mitogen-activated protein kinase (MAPK) pathways regulate many cellular functions including cell proliferation, differentiation, migration and apoptosis. We evaluate genetic variation in the c-Jun-N-terminal kinases, p38, and extracellular regulated kinases 1/2 MAPK-signaling pathways and colon and rectal cancer risk using data from population-based case-control studies (colon: n = 1555 cases, 1956 controls; rectal: n = 754 cases, 959 controls). We assess 19 genes (DUSP1, DUSP2, DUSP4, DUSP6, DUSP7, MAP2K1, MAP3K1, MAP3K2, MAP3K3, MAP3K7, MAP3K9, MAP3K10, MAP3K11, MAPK1, MAPK3, MAPK8, MAPK12, MAPK14 and RAF1). MAP2K1 rs8039880 [odds ratio (OR) = 0.57, 95% confidence interval (CI) = 0.38, 0.83; GG versus AA genotype] and MAP3K9 rs11625206 (OR = 1.41, 95% CI = 1.14, 1.76; recessive model) were associated with colon cancer (P (adj) value < 0.05). DUSP1 rs322351 (OR = 1.43, 95% CI = 1.09, 1.88; TT versus CC) and MAPK8 rs10857561 (OR = 1.48, 95% CI 1.08, 2.03; AA versus GG/GA) were associated with rectal cancer (P (adj) < 0.05). Aspirin/non-steroidal anti-inflammatory drug, cigarette smoking and body mass index interacted with several genes to alter cancer risk. Genetic variants had unique associations with KRAS, TP53 and CIMP+ tumors. DUSP2 rs1724120 [hazard rate ratio (HRR) = 0.72, 95%CI = 0.54, 0.96; AA versus GG/GA), MAP3K10 rs112956 (HRR = 1.40, 95% CI = 1.10, 1.76; CT/TT versus CC) and MAP3K11 (HRR = 1.76, 95% CI 1.18, 2.62 TT versus GG/GT) influenced survival after diagnosis with colon cancer; MAP2K1 rs8039880 (HRR = 2.53, 95% CI 1.34, 4.79 GG versus AG/GG) and Raf1 rs11923427 (HRR = 0.59 95% CI = 0.40, 0.86; AA versus TT/TA) were associated with rectal cancer survival. These data suggest that genetic variation in the MAPK-signaling pathway influences colorectal cancer risk and survival after diagnosis. Associations may be modified by lifestyle factors that influence inflammation and oxidative stress.

The concept of a CpG island methylator phenotype, or CIMP, quickly became the focus of several colorectal cancer studies describing its clinical and pathological features after its introduction in 1999 by Toyota and colleagues. Further characterization of CIMP in tumors lead to widespread acceptance of the concept, as expressed by Shen and Issa in their 2005 editorial, “CIMP, at last.” Since that time, extensive research efforts have brought great insights into the epidemiology and prognosis of CIMP+ tumors and other epigenetic mechanisms underlying tumorigenesis. With the advances in technology and subsequent cataloging of the human methylome in cancer and normal tissue, new directions in research to understand CIMP and its role in complex biological systems yield hope for future epigenetically based diagnostics and treatments.

Alcohol consumption is an established risk factor for colorectal cancer (CRC). However, while studies have consistently reported elevated risk of CRC among heavy drinkers, associations at moderate levels of alcohol consumption are less clear. We conducted a combined analysis of 16 studies of CRC to examine the shape of the alcohol–CRC association, investigate potential effect modifiers of the association, and examine differential effects of alcohol consumption by cancer anatomic site and stage. We collected information on alcohol consumption for 14,276 CRC cases and 15,802 controls from 5 case‐control and 11 nested case‐control studies of CRC. We compared adjusted logistic regression models with linear and restricted cubic splines to select a model that best fit the association between alcohol consumption and CRC. Study‐specific results were pooled using fixed‐effects meta‐analysis. Compared to non‐/occasional drinking (≤1 g/day), light/moderate drinking (up to 2 drinks/day) was associated with a decreased risk of CRC (odds ratio [OR]: 0.92, 95% confidence interval [CI]: 0.88–0.98, p = 0.005), heavy drinking (2–3 drinks/day) was not significantly associated with CRC risk (OR: 1.11, 95% CI: 0.99–1.24, p = 0.08) and very heavy drinking (more than 3 drinks/day) was associated with a significant increased risk (OR: 1.25, 95% CI: 1.11–1.40, p &lt; 0.001). We observed no evidence of interactions with lifestyle risk factors or of differences by cancer site or stage. These results provide further evidence that there is a J‐shaped association between alcohol consumption and CRC risk. This overall pattern was not significantly modified by other CRC risk factors and there was no effect heterogeneity by tumor site or stage.

<h3>Background & Aims</h3> Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. <h3>Methods</h3> Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) <h3>Results</h3> After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05–1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03–1.12; <i>P</i> = 3.3 × 10^–4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06–1.18; <i>P</i> = 4.2 × 10^–5). Colorectal cancer risk was associated with only 1 variant in the <i>IGFBP3</i> gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. <h3>Conclusions</h3> In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.

Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood.We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models.In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles.Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.

OBJECTIVES: MicroRNAs (miRNAs) are small, non-protein-coding RNA molecules that are commonly dysregulated in colorectal tumors. The objective of this study was to identify smaller subsets of highly predictive miRNAs. METHODS: Data come from population-based studies of colorectal cancer conducted in Utah and the Kaiser Permanente Medical Care Program. Tissue samples were available for 1,953 individuals, of which 1,894 had carcinoma tissue and 1,599 had normal mucosa available for statistical analysis. Agilent Human miRNA Microarray V.19.0 was used to generate miRNA expression profiles; validation of expression levels was carried out using quantitative PCR. We used random forest analysis and verified findings with logistic modeling in separate data sets. Important microRNAs are identified and bioinformatics tools are used to identify target genes and related biological pathways. RESULTS: We identified 16 miRNAs for colon and 17 miRNAs for rectal carcinoma that appear to differentiate between carcinoma and normal mucosa; of these, 12 were important for both colon and rectal cancer, hsa-miR-663b, hsa-miR-4539, hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-4506, hsa-miR-92a-3p, hsa-miR-93-5p, hsa-miR-145-5p, hsa-miR-3651, hsa-miR-378a-3p, and hsa-miR-378i. Estimated misclassification rates were low at 4.83% and 2.5% among colon and rectal observations, respectively. Among independent observations, logistic modeling reinforced the importance of these miRNAs, finding the primary principal components of their variation statistically significant (P<0.001 among both colon and rectal observations) and again producing low misclassification rates. Repeating our analysis without those miRNAs initially identified as important identified other important miRNAs; however, misclassification rates increased and distinctions between remaining miRNAs in terms of classification importance were reduced. CONCLUSIONS: Our data support the hypothesis that while many miRNAs are dysregulated between carcinoma and normal mucosa, smaller subsets of these miRNAs are useful and informative in discriminating between these tissues.

Apoptosis is genetically regulated and involves intrinsic and extrinsic pathways. We examined 133 genes within these pathways to identify whether they are expressed differently in colorectal carcinoma (CRC) and normal tissue (N = 217) and if they are associated with similar differential miRNA expression. Gene expression data (RNA-Seq) and miRNA expression data (Agilent Human miRNA Microarray V19.0) were generated. We focused on dysregulated genes with a fold change (FC) of > 1.50 or < 0.67, that were significant after adjustment for multiple comparisons. miRNA:mRNA seed-region matches were determined. Twenty-three genes were significantly downregulated (FC < 0.67) and 18 were significantly upregulated (FC > 1.50). Of these 41 genes, 11 were significantly associated with miRNA differential expression. BIRC5 had the greatest number of miRNA associations (14) and the most miRNAs with a seed-region match (10). Four of these matches, miR-145-5p, miR-150-5p, miR-195-5p, and miR-650, had a negative beta coefficient. CSF2RB was associated with ten total miRNAs (five with a seed-region match, and one miRNA, miR-92a-3p, with a negative beta coefficient). Of the three miRNAs associated with CTSS, miR-20b-5p, and miR-501-3p, had a seed-region match and a negative beta coefficient between miRNA:mRNA pairs. Several miRNAs that were associated with dysregulated gene expression, seed-region matches, and negative beta coefficients also were associated with CRC-specific survival. Our data suggest that miRNAs could influence several apoptosis-related genes. BIRC5, CTSS, and CSF2R all had seed-region matches with miRNAs that would favor apoptosis. Our study identifies several miRNA associated with apoptosis-related genes, that if validated, could be important therapeutic targets.

The PI3K/AKT‐signaling pathway is one of the most frequently activated signal‐transduction pathways in cancer. We examined how dysregulated gene expression is associated with miRNA expression in this pathway in colorectal cancer (CRC). We used data from 217 CRC cases to evaluate differential pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA‐Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analyzed. We focused on genes most associated with CRC (fold change (FC) of &gt;1.5 or &lt;0.67) that were statistically significant after adjustment for multiple comparisons. Of the 304 genes evaluated, 76 had a FC of &lt;0.67, and 57 had a FC of &gt;1.50; 47 of these genes were associated with miRNA differential expression. There were 145 mRNA:miRNA seed‐region matches of which 26 were inversely associated suggesting a greater likelihood of a direct association. Most miRNA:mRNA associations were with factors that stimulated the pathway. For instance, both IL6R and PDGFRA had inverse seed‐region matches with seven miRNAs, suggesting that these miRNAs have a direct effect on these genes and may be key elements in activation of the pathway. Other miRNA:mRNA associations with similar impact on the pathway were miR‐203a with ITGA4, miR‐6071 with ITGAV , and miR‐375 with THBS2, all genes involved in extracellular matrix function that activate PI3Ks. Gene expression in the PI3K/Akt‐signaling pathway is dysregulated in CRC. MiRNAs were associated with many of these dysregulated genes either directly or in an indirect manner.

The nuclear factor-kappa B (NF-κB) signalling pathway is a regulator of immune response and inflammation that has been implicated in the carcinogenic process. We examined differentially expressed genes in this pathway and miRNAs to determine associations with colorectal cancer (CRC).We used data from 217 CRC cases to evaluate differences in NF-κB signalling pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analysed. We evaluated genes most strongly associated and differentially expressed (fold change (FC) of > 1.5 or < 0.67) that were statistically significant after adjustment for multiple comparisons.Of the 92 genes evaluated, 22 were significantly downregulated and nine genes were significantly upregulated in all tumours. Two additional genes (CD14 and CSNK2A1) were dysregulated in MSS tumours and two genes (CARD11 and VCAM1) were downregulated and six genes were upregulated (LYN, TICAM2, ICAM1, IL1B, CCL4 and PTGS2) in MSI tumours. Sixteen of the 21 dysregulated genes were associated with 40 miRNAs. There were 76 miRNA:mRNA associations of which 38 had seed-region matches. Genes were associated with multiple miRNAs, with TNFSRF11A (RANK) being associated with 15 miRNAs. Likewise several miRNAs were associated with multiple genes (miR-150-5p with eight genes, miR-195-5p with four genes, miR-203a with five genes, miR-20b-5p with four genes, miR-650 with six genes and miR-92a-3p with five genes).Focusing on the genes and their associated miRNAs within the entire signalling pathway provides a comprehensive understanding of this complex pathway as it relates to CRC and offers insight into potential therapeutic agents.

We examined expression of genes in the p53-signaling pathway. We determine if genes that have significantly different expression in carcinoma tissue compared to normal mucosa also have significantly differentially expressed miRNAs. We utilize a sample of 217 CRC cases. We focused on fold change (FC) > 1.50 or <0.67 for genes and miRNAs, that were statistically significant after adjustment for multiple comparisons. We evaluated the linear association between the differential expression of miRNA and mRNA. miRNA:mRNA seed-region matches also were determined. Eleven dysregulated genes were associated with 37 dysregulated miRNAs; all were down-stream from the TP53 gene. MiR-150-5p (HR = 0.82) and miR-196b-5p (HR 0.73) significantly reduced the likelihood of dying from CRC when miRNA expression increased in rectal tumors. Our data suggest that activation of p53 from cellular stress, could target downstream genes that in turn could influence cell cycle arrest, apoptosis, and angiogenesis through mRNA:miRNA interactions.

An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.

Abstract Background Incidence of early-onset (younger than 50 years of age) colorectal cancer (CRC) is increasing in many countries. Thus, elucidating the role of traditional CRC risk factors in early-onset CRC is a high priority. We sought to determine whether risk factors associated with late-onset CRC were also linked to early-onset CRC and whether association patterns differed by anatomic subsite. Methods Using data pooled from 13 population-based studies, we studied 3767 CRC cases and 4049 controls aged younger than 50 years and 23 437 CRC cases and 35 311 controls aged 50 years and older. Using multivariable and multinomial logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) to assess the association between risk factors and early-onset CRC and by anatomic subsite. Results Early-onset CRC was associated with not regularly using nonsteroidal anti-inflammatory drugs (OR = 1.43, 95% CI = 1.21 to 1.68), greater red meat intake (OR = 1.10, 95% CI = 1.04 to 1.16), lower educational attainment (OR = 1.10, 95% CI = 1.04 to 1.16), alcohol abstinence (OR = 1.23, 95% CI = 1.08 to 1.39), and heavier alcohol use (OR = 1.25, 95% CI = 1.04 to 1.50). No factors exhibited a greater excess in early-onset compared with late-onset CRC. Evaluating risks by anatomic subsite, we found that lower total fiber intake was linked more strongly to rectal (OR = 1.30, 95% CI = 1.14 to 1.48) than colon cancer (OR = 1.14, 95% CI = 1.02 to 1.27; P = .04). Conclusion In this large study, we identified several nongenetic risk factors associated with early-onset CRC, providing a basis for targeted identification of those most at risk, which is imperative in mitigating the rising burden of this disease.

The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores.Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes.

Some previous studies have demonstrated significant results between Ki-ras mutations and tumor stage, survival, and/or other clinical variables, whereas others have not. We therefore evaluated the significance of codons 12 and 13 Ki-ras mutations in a large population-based study of 1413 individuals with colon cancer. Ki-ras mutations were identified in approximately 32% of tumors. Codon 12 mutations were significantly more common in proximal than distal tumors (29.1% versus 20.5%; P < 0.01) and in tumors of advanced stage. Tumors from men were more likely to have transition mutations and codon 12 G-->A mutations. After adjusting for age and stage, the codon 13 G-->A mutation was associated with a 40% (95% confidence interval, 0.95-2.0) increase in short-term mortality from colon cancer. In conclusion, this population-based study demonstrates important relationships between Ki-ras mutations and stage, survival, tumor location, and gender.

Although physical activity has been consistently inversely associated with colon cancer incidence, the association of physical activity with other diet and lifestyle factors that may influence this association is less well understood. Confounding and effect modification are examined to better understand the physical activity and colon cancer association.Based on hypothesized biological mechanisms whereby physical activity may alter risk of colon cancer, we evaluated confounding and effect modification using data collected as part of a case-control study of colon cancer (N = 1993 cases and 2410 controls). We examined associations between total energy intake, fiber, calcium, fruit and vegetables, red meat, whole grains as well as dietary patterns along with cigarette smoking, alcohol consumption, BMI, and use of aspirin and/or NSAIDs and physical activity.No confounding was observed for the physical activity and colon cancer association. However, differences in effects of diet and lifestyle factors were identified depending on level of physical activity. Most striking were statistically significant interactions between physical activity and high-risk dietary pattern and vegetable intake, in that the relative importance of diet was dependent on level of physical activity. The predictive model of colon cancer risk was improved by using an interaction term for physical activity and other variables, including BMI, cigarette smoking, energy intake, dietary fiber, dietary calcium, glycemic index, lutein, folate, vegetable intake, and high-risk diet rather than using models that included these variables as independent predictors with physical activity. In populations where activity levels are high, the estimate of risk associated with high vegetable intake was 0.9 (95% CI 0.6-1.3), whereas in more sedentary populations the estimate of risk associated with high vegetable intake was 0.6 (95% CI 0.5-0.9).Physical activity plays an important role in the etiology of colon cancer. Its significance is seen by its consistent association as an independent predictor of colon cancer as well as by its impact on the odds ratios associated with other factors. Given these observations, it is most probable that physical activity operates through multiple biological mechanisms that influence the carcinogenic process.

PURPOSE: It has been suggested that performing physical activity for at least 30 min on most days of the week will improve health. The purpose of this study was to assess the association between physical activity and colon cancer as it relates to this public health recommendation. METHODS: A large population-based case-control study of colon cancer was conducted. Study participants came from three areas of the United States: Northern California, Utah, and the Twin Cities Metropolitan Area in Minnesota. RESULTS: Long-term involvement in high levels of activity, equivalent to ⩾ 60 min of vigorous activity per session, was associated with decreased risk (odds ration [OR], 0.68; 95% confidence interval [CI] 0.52–0.87). The amount of time involved in the activity appeared to have a greater impact than the number of days per week that activities were performed. Those reporting the highest level of activity, as defined by both duration and vigorous intensity, were at the lowest risk (OR, 0.62; 95% CI, 0.52–0.75) relative to those who were sedentary; associations did not differ by age at diagnosis, site of the tumor within the colon, or sex. The inverse association between colon cancer and long-term vigorous leisure-time activity was slightly stronger among those without a family history of colorectal cancer than among those with a family history of colorectal cancer. From these data we estimate that 13% of colon cancer could be attributed to lack of vigorous leisure-time activity in the population; we estimate that 4.3 cases of colon cancer/100,000 population are prevented each year because people are involved in vigorous leisure-time physical activity. CONCLUSIONS: Data from this study suggest that a high level of vigorous leisure-time activity performed over the past 20 years was important in reducing colon cancer risk; the greatest inverse association was observed when activities were performed for longer periods of time per session for the past 20 years. These and other data indicate that it is important to identify ways to facilitate an increase in leisure-time physical activity within the population.

Some previous studies have reported an improved prognosis in sporadic colon cancers with microsatellite instability, whereas others have not. In addition, relatively few of those reporting an improved prognosis controlled for tumor stage or were population-based. Therefore, we evaluated the relationship between microsatellite instability and prognosis, tumor stage, and other clinical variables in a population-based study of 1026 individuals. Microsatellite instability was determined by the noncoding mononucleotide repeat BAT-26 and the coding mononucleotide repeat in transforming growth factor-beta receptor type II. Significant relationships were seen between microsatellite instability and proximal tumor location, female gender, young and old age at diagnosis, poor histological differentiation, and low tumor stage (P < 0.01). There was a significant relationship between microsatellite instability and improved prognosis, even after adjusting for stage, with a reduction in the risk of death attributable to colon cancer of approximately 60%. Most of this risk reduction occurred in individuals with American Joint Committee on Cancer stage III tumors, although transforming growth factor-beta receptor type II mutations were associated with a significant reduction in colon cancer death in tumors with distant metastases. We conclude that microsatellite instability in sporadic colon cancer is associated with an improved prognosis at the population level.

To describe methods used to computerize the diet history questionnaire developed for the Coronary Artery Risk Factor Development in Young Adult (CARDIA) study and to describe quality-control procedures used in conjunction with dietary assessment.The computerized diet history is being used in a case-control study. Because of the computerized nature of the questionnaire, we developed quality-control procedures that incorporate listening to an audiotape of the interview while visually reviewing recorded data.Three centers involved in a population-based epidemiologic study of colon cancer.Men and women between the ages of 30 and 79 years.Quality-control results showed that 100% of the computerized forms would be free of errors if the data were subjected to visual review only. Probing errors, which accounted for 47.3% of all errors, were the most commonly encountered errors. In probing errors the interviewer did not probe in a nondirective manner, or the interviewer failed to verify responses that might be considered questionable.The CARDIA diet history was computerized for use in epidemiologic studies of the association between diet and disease. Review of the audiotapes of the interviews showed that most errors made in obtaining a dietary assessment were not detectable from visual review of the data. Although the quality-control procedures were developed for a computerized diet history questionnaire, they are applicable to other dietary assessment methods.

A population-based case-control study was used to investigate associations between prostate cancer and cadmium exposure, longest industry held, and longest occupation held. The study included 358 men with newly diagnosed prostate cancer and 679 control men identified from the Utah population. Occupational exposures to cadmium were ascertained from self-reported data, through several a priori suspect industries and occupations, through an occupation-exposure linkage system, and through dietary food frequency questionnaires. Overall, cadmium exposure appeared to result in a small increased relative risk for prostate cancer, most apparent for aggressive tumors (OR = 1.7, CI = 1.0-3.1 for any occupational exposure, high dietary intake, or smoking cigarettes). Cases were more likely to have worked in the following industries: mining, paper and wood, medicine and science, and entertainment and recreation. Among men younger than 67, cases were also more likely to have worked in the food and tobacco industries (OR = 3.6, CI = 1.0-12.8). Cases were less likely to have worked in industries involved with glass, clay and stone, or rubber, plastics, and synthetics. Men employed as janitors and in other building service occupations showed increased relative risk for aggressive tumors (OR = 7.0, CI = 2.5-19.6). Agricultural occupations did not appear to be related to prostate cancer, although an increased relative risk for aggressive tumors was detected among younger men (OR = 2.6, CI = 0.6-12.1).

Abstract The role of dietary calcium as a protective factor in the etiology of colon cancer is reviewed by examining data from ecological and analytical epidemiological studies. Biological evidence that explains the mechanisms whereby calcium intake could alter risk of developing colon cancer is also presented. The data reviewed here in general support the hypothesis that dietary calcium is linked to colon cancer in a protective manner, and that it may be one component in the etiology of colon cancer which alters an individual's risk of developing the disease.

Studies of the etiology of colon cancer indicate that it is strongly associated with diet and lifestyle factors. The authors use data from a population-based study conducted in northern California, Utah, and Minnesota in 1991–1995 to determine lifestyle patterns and their association with colon cancer. Data obtained from 1,993 cases and 2,410 controls were grouped by using factor analyses to describe various aspects of lifestyle patterns. The first five lifestyle patterns for both men and women loaded heavily on dietary variables and were labeled: "Western," "moderation," "calcium/low-fat dairy, " "meat and mutagens, " and "nibblers, smoking, and coffee." Other important lifestyle patterns that emerged were labeled "body size," "medication and supplementation" "alcohol," and "physical activity." Among both men and women, the lifestyle characterized by high levels of physical activity was the most marked lifestyle associated with colon cancer (odds ratios = 0.42, 95% confidence interval: 0.32, 0.55 and odds ratio = 0.52, 95% confidence interval: 0.39, 0.69, for men and women, respectively) followed by medication and supplementation (odds ratio = 1.68, 95%confidence interval: 1.29, 2.18 and odds ratio = 1.63, 95% CI 1.23, 2.16, respectively). Other lifestyles that were associated with colon cancer were the Western lifestyle, the lifestyle characterized by large body size, and the one characterized by calcium and low-fat dairy. Different lifestyle patterns appear to have age- and tumor site-specific associations. Am J Epidemiol 1999;150:869-77.

Cultural differences in diet and lifestyle patterns probably contribute to cancer rates among ethnic groups in the United States. In this paper, we describe physical activity patterns of Hispanic and non-Hispanic white women living in the southwestern United States and the effects of these patterns on obesity.We use data from population-based controls (N = 2039) participating in the 4-Corner's Breast Cancer Study to evaluate associations between physical activity and language acculturation and the associated effects on obesity.The majority of both Hispanic and non-Hispanic white women did not perform 30 min of activity > or = 5 d x wk(-1), although a greater percentage of Hispanic women meet the goal if they reported higher levels of language acculturation. However, the type and intensity of activities performed by Hispanic and non-Hispanic women differed; Hispanic women reported more housework, dependent care giving, dancing, and work activity. Differences in activity patterns existed by level of language acculturation among Hispanic women. Hispanic women who had higher levels of language acculturation reported continued activity throughout their lives. Prevalence of obesity was greater among Hispanic than non-Hispanic white women for all levels of language acculturation. Women with intermediate levels of language acculturation had the greatest relative risk of obesity compared with non-Hispanic white women (odds ratio (OR) = 2.79, 95% confidence interval (CI) = 1.85-4.02); Hispanic women with higher levels of language acculturation also were at increased relative risk of obesity (OR = 1.78, 95% CI = 1.28-2.47).Interventions to increase physical activity among Hispanic women are needed to address the problems of physical inactivity and obesity in that population. Facilitating culturally relevant activities might be reasonable approaches to increasing physical activity.

Some studies have reported that p53 mutations or certain types of p53 mutation are associated with poor prognosis in colon cancer, while other studies have failed to show such a relationship. None of these previous studies was population-based. We therefore evaluated the prognostic significance of p53 mutations in a large, population-based study of 1,464 individuals with colon cancer from Utah and California. Mutations in exons 5-8 were detected by SSCP analysis, followed by sequencing of aberrant bands. p53 mutations were identified in colon cancers from 665 of 1,464 (45.4%) individuals. p53 mutations were significantly more common in distal tumors (p < 0.01), tumors of relatively high stage (p = 0.04), tumors without MSI (p < 0.01) and tumors without Ki-ras mutations (p < 0.01). In a univariate analysis, tumors with p53 mutations were associated with a significantly worse 5-year survival than those with wild-type p53 (53.4% vs. 58.8%, p = 0.04); significantly worse prognosis also was seen with missense mutations, transitions, transversions, mutations affecting the structure of the p53 molecule, mutations within the beta-sandwich motif and mutations in proximal tumors. In multivariate analyses, however, the only significant predictors of poor prognosis were G245 hot spot mutations (HRR = 2.16, 95% CI 1.06-4.40) and p53 mutations in proximal tumors (HRR = 1.34, 95% CI 1.07-1.63). We conclude that overall p53 mutational status is not an independent predictor of poor prognosis in colon cancer. However, specific classes of mutations, namely, the G245 hot spot mutation and mutations in proximal tumors, are related to significantly worse survival even after adjusting for age and stage.

Background: Lack of confidence in postpolypectomy surveillance guidelines may be a factor in the observed low adherence rates among providers. Objective: To assess the 2006 postpolypectomy colonoscopy surveillance guidelines, which recommend 3-year follow-up colonoscopy for individuals with high-risk adenomas (defined as ≥3 adenomas or any advanced adenomas) and 5- to 10-year follow-up for patients with 2 or fewer nonadvanced adenomas, who are considered to be at low risk. Design: Analysis of prospective data from the Polyp Prevention Trial. Setting: United States. Participants: 1905 patients who had colorectal adenomas removed at baseline screening or diagnostic colonoscopy and completed the trial. Measurements: Baseline adenoma characteristics, risk-stratified according to definitions used in the guidelines, were examined as predictors for advanced adenoma recurrence. Results: 125 patients (6.6%) had advanced and 629 (33.0%) had nonadvanced adenoma recurrence; 1151 (60.4%) had no recurrence within 4 years of follow-up. The probability of advanced adenoma recurrence was 0.09 (95% CI, 0.07 to 0.11) among patients with high-risk adenomas at baseline and 0.05 (CI, 0.04 to 0.06) among those with low-risk adenomas at baseline. The relative risk for advanced adenoma recurrence for patients with high-risk adenomas versus those with low-risk adenomas at baseline was 1.68 (CI, 1.19 to 2.38) when advanced adenoma recurrence was compared with no advanced adenoma recurrence and 1.76 (CI, 1.26 to 2.46) when advanced adenoma recurrence was compared with no adenoma recurrence. The c-statistics for these 2 comparisons were 0.68 and 0.72, respectively. Limitation: Participants were self-selected and had restrictions on the degree of obesity. Conclusion: Although the risk for recurrence of advanced adenoma within 4 years is greater for patients with high-risk adenomas at baseline than for those with low-risk adenomas, the discrimination of this risk stratification scheme is relatively low.

In this study we assessed the reliability of recall of physical activity. Study participants were members of the Coronary Artery Risk Development in Young Adult Study (CARDIA) cohort who reported physical activity at each CARDIA examination. In this study, we asked 81 participants to recall activity patterns for the year prior to 2 to 3 years ago so that we could compare recalled activity patterns to those reported 2 to 3 years ago (labeled as “distantly recalled”) as well as to activity patterns reported at the other CARDIA examinations. We found that distantly recalled physical activity patterns were highly correlated with those reported at the time of the examination where they were obtained (vigorous activity r = 0.84, moderate activity r = 0.64, and total activity r = 0.81). Distantly recalled activity was less highly associated with activity reported currently (vigorous activity r = 0.57, moderate activity r = 0.45, total activity r = 0.59). The activity recalled the best was jogging or running (r = 0.76) and the activity with the poorest recall was racket sports (r = 0.53). Distantly recalled physical activity also was related to resting pulse rate obtained during the time period of the recalled activity (r = −0.21). These findings suggest that people can recall activity patterns of several years ago with high reliability.