Xianghui Ning

Kidney cancer is one of the most common urological cancers worldwide, and kidney renal clear cell cancer (KIRC) is the major histologic subtype. Our previous study found that von-Hippel Lindau (VHL) gene mutation, the dominant reason for sporadic KIRC and hereditary kidney cancer-VHL syndrome, could affect VHL disease-related cancers development by inducing telomere shortening. However, the prognosis role of telomere-related genes in kidney cancer has not been well discussed. In this study, we obtained the telomere-related genes (TRGs) from TelNet. We obtained the clinical information and TRGs expression status of kidney cancer patients in The Cancer Genome Atlas (TCGA) database, The International Cancer Genome Consortium (ICGC) database, and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database. Totally 353 TRGs were differential between tumor and normal tissues in the TCGA-KIRC dataset. The total TCGA cohort was divided into discovery and validation TCGA cohorts and then using univariate cox regression, lasso regression, and multivariate cox regression method to conduct data analysis sequentially, ten TRGs (ISG15, RFC2, TRIM15, NEK6, PRKCQ, ATP1A1, ELOVL3, TUBB2B, PLCL1, NR1H3) risk model had been constructed finally. The kidney patients in the high TRGs risk group represented a worse outcome in the discovery TCGA cohort (p<0.001), and the result was validated by these four cohorts (validation TCGA cohort, total TCGA cohort, ICGC cohort, and CPTAC cohort). In addition, the TRGs risk score is an independent risk factor for kidney cancer in all these five cohorts. And the high TRGs risk group correlated with worse immune subtypes and higher tumor mutation burden in cancer tissues. In addition, the high TRGs risk group might benefit from receiving immune checkpoint inhibitors and targeted therapy agents. Moreover, the proteins NEK6, RF2, and ISG15 were upregulated in tumors both at the RNA and protein levels, while PLCL1 and PRKCQ were downregulated. The other five genes may display the contrary expression status at the RNA and protein levels. In conclusion, we have constructed a telomere-related genes risk model for predicting the outcomes of kidney cancer patients, and the model may be helpful in selecting treatment agents for kidney cancer patients.

Abstract The specific functions of gene products frequently depend on the developmental context in which they are expressed. Thus, studies on gene function will benefit from systems that allow for manipulation of gene expression within model systems where the developmental context is well defined. Here we describe a system that allows for genetically controlled overexpression of any gene of interest under normal physiological conditions in the early Drosophila embryo. This regulated expression is achieved through the use of Drosophila lines that express a maternal mRNA for the yeast transcription factor GAL4. Embryos derived from females that express GAL4 maternally activate GAL4-dependent UAS transgenes at uniform levels throughout the embryo during the blastoderm stage of embryogenesis. The expression levels can be quantitatively manipulated through the use of lines that have different levels of maternal GAL4 activity. Specific phenotypes are produced by expression of a number of different developmental regulators with this system, including genes that normally do not function during Drosophila embryogenesis. Analysis of the response to overexpression of runt provides evidence that this pair-rule segmentation gene has a direct role in repressing transcription of the segment-polarity gene engrailed. The maternal GAL4 system will have applications both for the measurement of gene activity in reverse genetic experiments as well as for the identification of genetic factors that have quantitative effects on gene function in vivo.

Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood.A total of 120 fresh clear cell RCC (ccRCC) specimens and 144 primary RCC and adjacent nonmalignant renal paraffin specimens were obtained from Department of Urology, Peking University First Hospital. Expression of CLDN7 in ccRCC tissues and cell lines were determined using bioinformatic data mining, quantitative real-time PCR (qRT-PCR), Western blotting and immunostaining. The clinical significance of CLDN7 expression and promoter DNA methylation status was analyzed in ccRCC patients from Peking University First Hospital and The Cancer Genome Atlas. Additionally, the methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed. Biological functions of CLDN7 were investigated by examining cell proliferation using MTS assays and EdU incorporation assays, cell migration by in vitro wound healing assays and transwell migration assays, cell invasion by transwell invasion assays, and cell apoptosis by flow cytometry. Mouse model experiments were performed to confirm the effects of CLDN7 on tumor growth and metastasis in vivo. The molecular mechanism of CLDN7 function was investigated using gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, Western blot and immunostaining in vitro and in vivo.Our findings revealed that CLDN7 is frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Interestingly, hypermethylation of the CLDN7 promoter was related to advanced ccRCC status and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. Additionally, GSEA and RNA-Seq results showed that CLDN7 had negative effects in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways. These results were validated by qRT-PCR, Western blot and immunostaining.We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC.

Von Hippel–Lindau (VHL) disease is an autosomal dominant familial cancer syndrome caused by germline mutations in VHL tumor suppressor gene. It is characterized by hemangioblastoma in central nervous system and retina, renal cell carcinoma or cyst, pheochromocytoma, pancreatic cyst and tumor, endolymphatic-sac tumor, and papillary cystadenoma in epididymis and broad ligament. Here, we used PCR-direct sequencing and universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) to detect VHL mutations in 16 patients clinically diagnosed with VHL disease. PCR-direct sequencing detected 12 germline mutations (75%, 12/16), in which a novel mutation of c.451A>T/p.Ile151Phe found in one proband had not been reported previously. UPQFM-PCR found two large deletions (12.5%, 2/16). The two remaining patients carried non-typical disease-causing mutations, including one silent mutation (c.481C>A/p.Arg161Arg) and one mutation in 3′-UTR (c.642+70C>A). Remarkably, 56.3% (9/16) probands did not have family history of VHL disease, suggesting the higher frequency of de novo mutations in Chinese patients. We also summarized Chinese VHL disease patients with VHL mutation findings published in the literature to provide information about the spectrum of VHL mutations in Chinese VHL disease patients.

The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. The aim of this study was to investigate the critical role of Coiled-coil domain-containing protein 34 (CCDC34) in bladder carcinogenesis, which has never been reported to date. Here, we found CCDC34 expression was elevated in bladder cancer tissues and cell lines. The knockdown of CCDC34 via lentivirus-mediated siRNA significantly suppressed bladder cancer cells proliferation and migration, and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro. In addition, CCDC34 knockdown suppressed bladder tumor growth in nude mice. Moreover, CCDC34 silencing decreased the phosphorylation of MEK, ERK1/2, JNK, p38 and Akt, and the expressions of c-Raf and c-Jun, indicating MAPK and AKT pathways (ERK/MAPK, p38/MAPK, JNK/MAPK and PI3K/Akt) might be involved in CCDC34 regulation of bladder cancer cell proliferation and migration. Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis and it may serve as a biomarker or even a therapeutic target for bladder cancer.

Multilocular cystic clear cell renal cell neoplasm of low malignant potential or multilocular cystic renal cell carcinoma (MCRCC) is a rare distinct subtype of clear cell renal cell carcinoma (RCC). No large series of cases have been reported to date. The present study aimed to characterize the clinical and pathologic features of MCRCC.From January 2006 to December 2014, 76 cases were identified as MCRCC among 4345 patients with RCC at our institution. Their clinical and characteristics, surgical management, pathologic features, and outcomes were retrospectively reviewed.The incidence of MCRCC in our patients with RCC was 1.7%. The mean age at diagnosis was 46.7 ± 10.5 years (range, 18 to 80 years). Most cases showed no symptoms. Nuclear grade was unrelated to the tumor size (P = .112) and TNM stage (P = .451). Of these 76 patients, 66 (86.8%) were followed up for a median of 52 months, and no tumor recurrence or metastasis was found.The incidence of MCRCC in patients with RCC is low. The nuclear grade of MCRCC cases was unrelated to the tumor size and TNM stage, suggesting that the current stage criteria might not suitable for this lesion. Patients with MCRCC have an excellent prognosis; thus, the follow-up interval after surgery can be longer to minimize unnecessary examinations.

Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

Abstract Von Hippel–Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent–child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent–child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P &amp;lt; 0.001) in the 10 parent–child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P = 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease. Cancer Res; 74(14); 3802–9. ©2014 AACR.

von Hippel-Lindau (VHL) disease is caused by mutations in the VHL gene and demonstrates marked phenotypic variability. Genotype-phenotype correlations in Chinese VHL patients have been unclear. To establish genotype-phenotype correlations in Chinese VHL patients, we collected VHL mutations and phenotypes of 291 patients with VHL disease from 115 unrelated families. Genotype-phenotype correlations at mutation type level, mutation region level, and mutation codon level were analyzed by Kaplan-Meier curves and Cox regression models. We found missense mutations conferred an increased risk of pheochromocytoma developments, but a decreased risk of central nervous system hemangioblastomas (CHBs) and pancreatic lesions. Patients with VHL deletions were more prone to developing retinal angiomas. Renal cell carcinomas were more frequent in nonsense, frameshift or splice-site mutations. Mutations in Exon 2 conferred a higher risk and earlier diagnostic age of CHBs than mutations in other exons (HR = 1.684, 95% CI 1.082-2.620, p = 0.021; 27.0 ± 9.7 years versus 32.8 ± 11.7 years, p = 0.024), while patients with mutations in Exon 3 were more prone to developing pheochromocytomas (HR = 2.760, 95% CI 1.419-5.370, p = 0.003). Mutations at codon 80 or codon167 conferred significantly higher risks of pheochromocytomas than other mutations (HR = 4.678, 95% CI 1.392-15.724, p = 0.013; HR = 4.683, 95% CI 2.515-8.719, p < 0.001 respectively). In conclusion, VHL mutation types, mutation regions and mutation codons can act as phenotypic predictors of VHL disease. Mutation regions and mutation codons may aid in directed surveillance and monitoring of VHL patients.

Historically, von Hippel-Lindau (VHL) disease is characterised by a poor survival. Although genotype-phenotype correlation has been described in many studies, the risk factors for VHL survival remain unclear. This study aims to evaluate the median survival of Chinese patients with VHL disease and explore whether VHL survival is influenced by genetic and clinical factors.In this retrospective study, we recruited 340 patients from 127 VHL families. Kaplan-Meier plot and Cox regression model were used to evaluate the median survival and assess how survival was influenced by birth year, birth order, sex, family history, mutation type, onset age and first presenting symptom.The estimated median life expectancy for Chinese patients with VHL disease was 62 years. Patients with early-onset age, positive family history and truncating mutation types had poorer overall and VHL-related survival. Patients with haemangioblastoma as their first presenting symptom were related to a higher risk of death from central nervous system haemangioblastoma than those with abdominal lesions (HR 8.84, 95% CI 2.04 to 38.37, P=0.004).This largest VHL survival analysis indicates that onset age, family history, mutation type and first presenting symptom have an effect on the survival of patients with VHL disease, which is helpful to genetic counselling and clinical decision-making.

Co-expression of erythropoietin (Epo) and erythropoietin receptor (EpoR) has been found in various non-hematopoietic cancers including hereditary and sporadic renal cell carcinomas (RCC), but the Epo/EpoR autocrine and paracrine mechanisms in tumor progression have not yet been identified. In this study, we used RNA interference method to down-regulate EpoR to investigate the function of Epo/EpoR pathway in human RCC cells. Epo and EpoR co-expressed in primary renal cancer cells and 6 human RCC cell lines. EpoR signaling was constitutionally phosphorylated in primary renal cancer cells, 786-0 and Caki-1 cells, and recombinant human Epo (rhEpo) stimulation had no significant effects on further phosphorylation of EpoR pathway, proliferation, and invasiveness of the cells. Down-regulation of EpoR expression in 786-0 cells by lentivirus-introduced siRNA resulted in inhibition of growth and invasiveness in vitro and in vivo, and promotion of cell apoptosis. In addition, rhEpo stimulation slightly antagonized the anti-tumor effect of Sunitinib on 786-0 cells. Sunitinib could induce more apoptotic cells in 786-0 cells with knockdown EpoR expression. Our results suggested that Epo/EpoR pathway was involved in cell growth, invasion, survival, and sensitivity to the multi-kinases inhibitor Sunitinib in RCC cells.

The present study aimed to establish a hypoxia related genes model to predict the prognosis of kidney clear cell carcinoma (KIRC) patients using data accessed from The Cancer Genome Atlas (TCGA) database and International Cancer Genome Consortium (ICGC) database.Patients' data were downloaded from the TCGA and ICGC databases, and hypoxia related genes were accessed from the Molecular Signatures Database. The differentially expressed genes were evaluated and then the differential expressions hypoxia genes were screened. The TCGA cohort was randomly divided into a discovery TCGA cohort and a validation TCGA cohort. The discovery TCGA cohort was used for constructing the hypoxia genes risk model through Lasso regression, univariate and multivariate Cox regression analysis. Receiver operating characteristic (ROC) curves were used to assess the reliability and sensitivity of our model. Then, we established a nomogram to predict the probable one-, three-, and five-year overall survival rates. Lastly, the Tumor Immune Dysfunction and Exclusion (TIDE) score of patients was calculated.We established a six hypoxia-related gene prognostic model of KIRC patients in the TCGA database and validated in the ICGC database. The patients with high riskscore present poorer prognosis than those with low riskscore in the three TCGA cohorts and ICGC cohort. ROC curves show our six-gene model with a robust predictive capability in these four cohorts. In addition, we constructed a nomogram for KIRC patients in the TCGA database. Finally, the high risk-group had a high TIDE score than the patients with low riskscore.We established a six hypoxia-related gene risk model for independent prediction of the prognosis of KIRC patients was established and constructed a robust nomogram. The different riskscores might be a biomarker for immunotherapy strategy.

Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis. Recently, the catalytic activity-independent function of FBP1, hypoxia-induced factor (HIF) repression in the nucleus, was identified. The aim of the present study was to investigate the association between FBP1 and hypoxia-related gene expression in clear cell renal cell carcinoma (ccRCC). The protein expression levels of FBP1, HIF-1α, HIF-2α, erythropoietin (EPO) and carbonic anhydrase IX (CA9) were assessed by immunohistochemical staining of ccRCC paraffin blocks from 123 patients using the tissue microarray technique. The expression level of FBP1 was then correlated with various clinicopathological factors, and the protein expression levels of HIF-1α, HIF-2α, EPO and CA9. Clinicopathological factors, including age, gender, T stage and Fuhrman grade, were not significantly different between patients with low and high FBP1 expression in ccRCC (P>0.05). FBP1 protein expression level was significantly correlated with the expression levels of HIF-1α (P=0.005) and EPO (P=0.010), but not significantly correlated with the expression levels of HIF-2α (P=0.123) and CA9 (P=0.513) in ccRCC tissues. The current findings confirm the association between FBP1 and hypoxia-related gene expression, and may facilitate understanding of the mechanisms of ccRCC tumorigenesis.

Renal cell carcinoma is one of the most common urological tumors. The role of programmed cell death 1 ligand 1 (PD-L1) in renal cell carcinomas in predicting outcome of the patients is yet unclear. We analyzed the clinical and RNA-seq data of 522 kidney clear cell cancer, 259 kidney papillary cell carcinoma and 66 kidney chromophobe patients from The Cancer Genome Atlas (TCGA) database. In kidney clear cell cancer patients with high PD-L1 mRNA level and low PD-L1 mRNA level in tumors, the median overall survival periods were 45.0 and 37.1 months respectively (p=0.002). Multivariate Cox regression tests found that PD-L1 mRNA level in tumor was an independent predictor for overall survival status in kidney clear cell cancer patients (HR=0.7, 95% CI 0.5-0.9, p=0.007). However, no significant difference in overall survival status was found between high and low PD-L1 groups in kidney papillary cell carcinoma and kidney chromophobe cohorts. Gene-set enrichment analysis on the data from databases of TCGA and GSE53757 dataset in Gene Expression Omnibus databases showed that several pathways relating to immunological functions were activated in kidney clear cell cancers with high PD-L1 mRNA expression, and glycolysis and epithelial-mesenchymal transition pathways relating to tumor progression and metastasis were increased in kidney clear cell cancers with low PD-L1 mRNA level. In conclusion, higher PD-L1 mRNA level in kidney clear cell cancer tissues was associated with a favorable outcome due to the higher immunological responses in tumor tissues.

von Hippel–Lindau ( VHL ) disease is an inheritable multisystem tumor syndrome characterized by multiple benign and malignant tumors affecting multiple organs. VHL is the result of a germline mutation in the VHL tumor suppressor gene. Molecular genomic analysis routinely confirms the clinical diagnosis. However, the use of molecular diagnostic methods can often be insufficient for the detection of mosaic germline VHL mutations, making the diagnosis of some cases of VHL difficult. Here, we report the case of a VHL mosaic patient with bilateral renal lesions in the absence of other VHL ‐associated lesions. A VHL mutation was not originally detected by routine molecular testing. Nonetheless, the detection of a heterozygous c. 194C &gt;G (p. Ser65Trp ) VHL mutation in the patient's daughter prompted further genetic assessment and eventually resulted in the finding of a mosaic c. 194C &gt;G (p. Ser65Trp ) VHL mutation in the patient. The mutation rate was 18.8 ± 3.84% in peripheral leukocytes. As the frequency of VHL mosaicism remains underdetermined, the possibility of a diagnosis of mosaic VHL should be considered in patients with both typical and atypical VHL ‐associated manifestations.

The purpose of this study was to investigate the clinicopathologic features, treatment, and prognosis of sporadic bilateral renal cell carcinoma (RCC).A total of 148 patients with sporadic bilateral RCC treated in our center from June 1986 to December 2015 were included in this retrospective study. Their clinicopathologic features and treatments were evaluated. The survival and prognostic factors were assessed based on data from follow-up.The median age was 54 years (range, 31-78 years). There were 88 patients with synchronous bilateral RCC and 60 with metachronous bilateral RCC. The median interval between bilateral tumors of metachronous bilateral RCC was 75.5 months. There was no significant difference in tumor size, nuclear grade, or T stage between metachronous tumors (P = .385, P = .544, and P = .263, respectively). Of 148 patients, 124 patients underwent bilateral surgery, 16 underwent unilateral surgery, and 8 patients did not undergo surgery. Of the 317 tumors with pathologic results, 297 (93.7%) were clear-cell subtype. A total of 136 (91.9%) patients were followed-up, and the median follow-up period was 77 months (range, 2-398 months). During follow-up, 38 (27.9%) patients died. The 5-year overall survival rate was 85.9%. The median survival time of patients with no surgery was 5 months. Older age (P = .001), bilateral nonoperative treatment (P < .001), higher T stage (P < .001), and multifocality (P = .02) were related to worse prognosis in multivariate analysis.In metachronous bilateral RCC, the latter occurrence does not bear a significantly worse pathologic biology. The prognosis of sporadic bilateral RCC with no surgery is poor. The overall oncologic results of patients with sporadic bilateral RCC are comparable with that of patients with unilateral RCC.

Abstract Von Hippel‐Lindau ( VHL ) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age‐related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age‐related risks for the five major VHL ‐associated tumors were evaluated using Kaplan–Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls( P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age‐adjusted telomere length ≤ 0.44) suffered higher age‐related risks for VHL ‐associated central nervous system hemangioblastomas ( HR : 1.879, P = 0.004), renal cell carcinoma ( HR : 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors ( HR : 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age‐related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL ‐associated tumors.

Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region.The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed.A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, pmeta = 7.02×10-11, OR 1.19, 95%CI 1.13-1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression.The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.

Objective To observe the clinical and molecular characteristics in Chinese Von Hippel-Lindau (VHL) disease patients. Materials and Methods Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, we examined mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012. Results Of the 19 VHL disease families, VHL disease type I was identified in 14 families, type IIA in 1 family, and type IIB in 4 families. Mutation detection found missense point mutations in 7 families, nonsense point mutations in 3 families, small indels in 6 families, and large deletions in 3 families. Novel mutations were detected in 9 families (47.4%), in which 6 had no family history; previously reported mutations were found in 10 families, in which 3 had no family history. Conclusion The prevalence of novel mutations without family history was higher in this group of patients, presumably demonstrating the higher prevalence of de novo mutations in VHL gene in Chinese VHL disease patients. To observe the clinical and molecular characteristics in Chinese Von Hippel-Lindau (VHL) disease patients. Using polymerase chain reaction (PCR)-direct sequencing and universal primer quantitative fluorescent multiplex–PCR, we examined mutations in VHL gene in 19 VHL disease families recruited from the Department of Urology, Peking University First Hospital in the period from 2009 to 2012. Of the 19 VHL disease families, VHL disease type I was identified in 14 families, type IIA in 1 family, and type IIB in 4 families. Mutation detection found missense point mutations in 7 families, nonsense point mutations in 3 families, small indels in 6 families, and large deletions in 3 families. Novel mutations were detected in 9 families (47.4%), in which 6 had no family history; previously reported mutations were found in 10 families, in which 3 had no family history. The prevalence of novel mutations without family history was higher in this group of patients, presumably demonstrating the higher prevalence of de novo mutations in VHL gene in Chinese VHL disease patients.

Renal arterial pseudoaneurysm (RAP) and renal arteriovenous fistula (RAVF) are rare but can cause fatal bleeding.A retrospective review was conducted for patients undergoing partial nephrectomy (PN) in our department. The clinical features and treatment methods were analysed, and the relationships between RAP/RAVF and the surgical methods and R.E.N.A.L. score were investigated.Eleven patients were diagnosed with RAP/RAVF (9 with RAP and 2 with RAVF). The incidence of RAP/RAVF after laparoscopic PN showed no significant difference compared to that after open PN (p = 0.47). A low R.E.N.A.L. score was present in 6 patients, while an intermediate/high score was present in the other 5 patients. The major clinical manifestations included haematuria and haemorrhagic shock, and the median time of occurrence was 8 days after the operation. Six patients underwent an ultrasound examination. Of the 4 patients who underwent enhanced CT, 2 patients were diagnosed with RAP. All 11 patients were diagnosed by renal angiography and were cured after super-selective arterial embolization. The serum creatinine levels before and after embolization showed no significant differences (p = 0.14).RAP/RAVF may not have any relationship with the surgical procedure or R.E.N.A.L. score. Renal angiography and super-selective arterial embolization are the preferred methods for diagnosing and treating RAP/RAVF.

von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p = 0.834) and between first-born patients and the other siblings (p = 0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

The aim of the study is to evaluate the role of cytoreductive nephrectomy (CN) with thrombectomy before targeted molecular therapy (TMT) on survival in metastatic renal cell carcinoma (mRCC) with venous tumor thrombus.We performed a retrospective analysis of 47 patients treated in our center from April 2008 to October 2014. In the study, 20 patients underwent CN with thrombectomy followed by targeted therapy (group 1); 15 patients received targeted therapy alone (group 2); and 12 patients underwent CN with thrombectomy alone (group 3). The overall survival (OS) and cancer-specific survival (CSS) were calculated according to the Kaplan-Meier survival curve method, and prognostic variables were assessed by Cox regression analyses.The median follow-up times of group 1, group 2, and group 3 were 24.5, 12, and 6.5 months, respectively. During follow-up, in both group 1 and group 3, 12 patients died. In group 2, 14 patients died. The median OS of group 1, group 2, and group 3 was 22, 12, and 6 months, respectively (P < 0.001). Compared with surgery alone and targeted therapy alone, patients with cytoreductive surgery before targeted therapy had statistically better survival benefits (P < 0.001, P = 0.009, respectively). On univariate analysis, the number of metastatic sites (P = 0.004) was a statistically significant prognostic factor influencing OS.Our single-center experience showed that CN with thrombectomy before targeted therapy improved the survival of patients with mRCC with venous tumor thrombus. The number of metastatic sites was an independent prognostic factor influencing OS.

Bladder cancer (BLCA) is the most common urinary tract tumor and is the 11th most malignant cancer worldwide. With the development of in-depth multisystem sequencing, an increasing number of prognostic molecular markers have been identified. In this study, we focused on the role of protein-coding gene methylation in the prognosis of BLCA. We downloaded BLCA clinical and methylation data from The Cancer Genome Atlas (TCGA) database and used this information to identify differentially methylated genes and construct a survival model using lasso regression. We assessed 365 cases, with complete information regarding survival status, survival time longer than 30 days, age, gender, and tumor characteristics (grade, stage, T, M, N), in our study. We identified 353 differentially methylated genes, including 50 hypomethylated genes and 303 hypermethylated genes. After annotation, a total of 227 genes were differentially expressed. Of these, 165 were protein-coding genes. Three genes (zinc finger protein 382 (ZNF382), galanin receptor 1 (GALR1), and structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1)) were selected for the final risk model. Patients with higher-risk scores represent poorer survival than patients with lower-risk scores in the training set ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M1"> <mtext>HR</mtext> <mo>=</mo> <mn>2.37</mn> </math> , 95% CI 1.43-3.94, <math xmlns="http://www.w3.org/1998/Math/MathML" id="M2"> <mi>p</mi> <mo>=</mo> <mn>0.001</mn> </math> ), in the testing group ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M3"> <mtext>HR</mtext> <mo>=</mo> <mn>1.85</mn> </math> , 95% CI 1.16-2.94, <math xmlns="http://www.w3.org/1998/Math/MathML" id="M4"> <mi>p</mi> <mo>=</mo> <mn>0.01</mn> </math> ), and in the total cohort ( <math xmlns="http://www.w3.org/1998/Math/MathML" id="M5"> <mtext>HR</mtext> <mo>=</mo> <mn>2.06</mn> </math> , 95% CI 1.46-2.90, <math xmlns="http://www.w3.org/1998/Math/MathML" id="M6"> <mi>p</mi> <mo>&lt;</mo> <mn>0.001</mn> </math> ). Further univariate and multivariate analyses using the Cox regression method were conducted in these three groups, respectively. All the results indicated that risk score was an independent risk factor for BLCA. Our study screened the different methylation protein-coding genes in the BLCA tissues and constructed a robust risk model for predicting the outcome of BLCA patients. Moreover, these three genes may function in the mechanism of development and progression of BLCA, which should be fully clarified in the future.

Birt-Hogg-Dubé (BHD) syndrome, a hereditary renal cancer syndrome caused by mutations in the folliculin (FLCN) gene, is characterized by the presence of fibrofolliculomas, pulmonary cysts, spontaneous pneumothorax, and renal cell carcinoma (RCC). Few BHD syndrome cases have been reported in Asian countries, and cutaneous presentations are relatively rare in Asian patients. Asian BHD patients may be misdiagnosed due to their atypical manifestations. Here, we report two Chinese BHD patients with novel FLCN mutations (c.946-947delAG in exon 9 and c.770-772delCCT in exon 7). Both of them had RCC and spontaneous pneumothorax without fibrofolliculomas. In patients with RCC and pulmonary cysts but without cutaneous lesions, screening for mutations in the FLCN gene should be performed, especially for those with a family history of RCC or pulmonary cysts (pneumothorax).

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with strong genetic disposition with more than 100 susceptibility genes identified until now. However, our knowledge on SLE genetic background is still limited. The present study was aimed at evaluating the role of single nucleotide polymorphisms (SNPs) in SCUBE3, a TGF-β signaling activator, with SLE susceptibility in Chinese populations.A total of 2801 individuals (490 cases and 493 controls from GWAS cohort and 1003 cases and 815 controls from our cohort) were enrolled, and SNPs located 10 kb up- and downstream of SCUBE3 (chr6:35182190-35218609) were included in the genetic association study. Multiple layers of bioinformatics were conducted, and the levels of SCUBE3 expression were confirmed.Of the 31 SNPs in SCUBE3 tested, 24 SNPs were significantly associated with SLE at p ≤ 0.05. The top locus was rs1888822 with p = 8.74∗10-6 in the discovery cohort and was confirmed by the replication cohort with p = 0.012. Additionally, the levels of SCUBE3 mRNA expression were significantly lower in patients with SLE comparing with healthy controls (p = 4.28∗10-4). Further expression data from ArrayExpress showed that the expression of SCUBE3 was also lower in CD3+ T cells and B cells from patients with SLE.Our research revealed that variants in SCUBE3, which encode SCUBE3 as a TGF-β signaling activator, can be considered as a new genetic susceptibility factor for systemic lupus erythematosus. And the reduced mRNA expression of SCUBE3 was first reported in patients with SLE.

Introduction: Kidney cancer is one of the most common and lethal urological malignancies. Discovering a biomarker that can predict prognosis and potential drug treatment sensitivity is necessary for managing patients with kidney cancer. SUMOylation is a type of posttranslational modification that could impact many tumor-related pathways through the mediation of SUMOylation substrates. In addition, enzymes that participate in the process of SUMOylation can also influence tumorigenesis and development. Methods: We analyzed the clinical and molecular data which were obtanied from three databases, The Cancer Genome Atlas (TCGA), the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC), and ArrayExpress. Results: Through analysis of differentially expressed RNA based on the total TCGA-KIRC cohort, it was found that 29 SUMOylation genes were abnormally expressed, of which 17 genes were upregulated and 12 genes were downregulated in kidney cancer tissues. A SUMOylation risk model was built based on the discovery TCGA cohort and then validated successfully in the validation TCGA cohort, total TCGA cohort, CPTAC cohort, and E-TMAB-1980 cohort. Furthermore, the SUMOylation risk score was analyzed as an independent risk factor in all five cohorts, and a nomogram was constructed. Tumor tissues in different SUMOylation risk groups showed different immune statuses and varying sensitivity to the targeted drug treatment. Discussion: In conclusion, we examined the RNA expression status of SUMOylation genes in kidney cancer tissues and developed and validated a prognostic model for predicting kidney cancer outcomes using three databases and five cohorts. Furthermore, the SUMOylation model can serve as a biomarker for selecting appropriate therapeutic drugs for kidney cancer patients based on their RNA expression.

Systemic lupus erythematosus (SLE) is a typical autoimmune disease with a strong genetic disposition. Genetic studies have revealed that single-nucleotide polymorphisms (SNPs) in zinc finger protein (ZNF)-coding genes are associated with susceptibility to autoimmune diseases, including SLE. The objective of the current study was to evaluate the correlation between ZNF76 gene polymorphisms and SLE risk in Chinese populations. A total of 2801 individuals (1493 cases and 1308 controls) of Chinese Han origin were included in this two-stage genetic association study. The expression of ZNF76 was evaluated, and integrated bioinformatic analysis was also conducted. The results showed that 28 SNPs were associated with SLE susceptibility in the GWAS cohort, and the association of rs10947540 was successfully replicated in the independent replication cohort (Preplication = 1.60 × 10-2, OR 1.19, 95% CI 1.03-1.37). After meta-analysis, the association between rs10947540 and SLE was pronounced (Pmeta = 9.62 × 10-6, OR 1.29, 95% CI 1.15-1.44). Stratified analysis suggested that ZNF76 rs10947540 C carriers were more likely to develop relatively high levels of serum creatinine (Scr) than noncarriers (CC + CT vs. TT, p = 9.94 × 10-4). The bioinformatic analysis revealed that ZNF76 rs10947540 was annotated as an eQTL and that rs10947540 was correlated with decreased expression of ZNF76. Remarkably, significantly reduced expression of ZNF76 was confirmed by expression data from both our laboratory and an array-based expression database. Taken together, these results suggest that ZNF76 rs10947540 is a possible susceptibility factor associated with SLE susceptibility. The mechanism underlying the relationship between ZNF76 and SLE pathogenesis still requires further investigation.

A recent genome-wide association study (GWAS) of Asian ancestry reported that single nucleotide polymorphism (SNP) in TERT (telomerase reverse transcriptase) was associated with systemic lupus erythematosus (SLE). TERT has a critical role in maintaining the chromosomal stability and the length of telomere. Given that only a small portion of the genetic heritability of SLE has been explained so far, we aimed to identify novel loci in telomere-related genes responsible for SLE susceptibility in Chinese populations. We performed a comprehensive genetic association analysis of SLE with telomere-related genes. To identify functional significance, we analyzed the publicly available HaploReg v4.1 and RegulomeDB databases. Differential gene expression analysis was also performed using ArrayExpress. A novel signal of PINX1 rs6984094 was identified (Pdiscovery = 4.13 × 10-2, OR = 0.58, 95% CI 0.35-0.98) and successfully replicated (Preplication = 5.73 × 10-3, OR = 0.45, 95% CI 0.26-0.81). Multiple layers of functional analysis suggested that the PINX1 rs6984094 risk T allele exhibited increased nuclear protein binding. We also observed an increased expression of PINX1 mRNA in peripheral blood mononuclear cells from SLE patients compared with healthy controls. Overall, we observed a novel genetic association between PINX1 (encodes the PinX1 protein, an inhibitory telomerase enzyme that lengthens telomeres) and SLE susceptibility in Chinese populations.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by apoptotic clearance deficiency provoking autoimmune responses and leading to multiple organ damage. PPAR-δ, encoded by the PPARD gene, was induced in macrophages promoting the timely disposal of apoptotic cells. Biological studies had provided solid foundation of PPARD involvement in SLE; it is worthwhile to further explore the genetic contribution of PPARD to SLE.We performed a discovery-replication genetic association study. The discovery study was based on previous reported GWAS data. And the replication study was conducted in 1003 SLE patients and 815 healthy controls from Henan, Middle East of China. Further, we analyzed the eQTL effect to identify possible functional significance.In the genetic association analysis, we observed significant association between the risk C allele of rs4713853 (p = 0.03, OR 1.167, 95% CI 1.015-1.341) and increased SLE susceptibility. Moreover, individuals with the risk C allele were associated with lower expression of PPARD and DEF6. Our clinical analysis showed that SLE patients with the risk C allele of rs4713853 were more likely to present a higher proportion of anti-Sm antibody presence (CC+CT vs. TT, 20.0% vs. 14.2%, p = 0.039) and higher level of Scr (median inter quarter range CC+CT vs. TT, 56 48-71 vs. 54 46-64 μmol/L, p = 0.002).In conclusion, our study identified a novel association between PPARD rs4713853 and SLE susceptibility in Chinese populations. By integrating multiple layers of analysis, we suggested that PPARD might be a main candidate in the pathogenesis of SLE.

Objective Fructose-1,6-bisphosphatase (FBP1) is often known as a rate-limiting enzyme in gluconeogenesis. Recently, its catalytic activity-independent function, repress hypoxia induced factor (HIF) in the nucleus, was identified. The aim of this study was to investigate the relationship between FBP1 and hypoxia related genes expression in clear cell renal cell carcinoma (ccRCC).

Objective Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families.

Objective Although VHL gene is well-known as the most important tumor suppressor gene in renal cell carcinoma (RCC), the exact mechanism of VHL gene missense mutation in the pathogenesis of RCC is unclear. We studied on the mechanism of VHL gene missense mutation in the function loss of VHL protein (pVHL), and discussed the possibility of pVHL as a new therapeutic target of RCC.

Objective Specialized stromal tumors of the prostate include stromal sarcoma and stromal tumors of uncertain malignant potential (STUMP). They are relatively rare and the clinical and prognostic features are unclear. Our study investigated diagnosis, treatment and prognosis of the disease.

Objective We investigated the clinical markers for the prediction of residual tumors at repeat transurethral resection (re-TUR) for patients with T1 bladder cancer and evaluated the effect of the residual tumor on the prognosis of the disease.

Objective To explore the optimal methods of diagnosis and treatment for renal arterial pseudoaneurysm (RAP) and renal arteriovenous fistula (RAVF) following partial nephrectomy.

Objective Multilocular cystic renal cell carcinoma (MCRCC) is a distinct subtype of clear cell renal cell carcinoma. Different from other types of renal cancers, MCRCC has a favorable outcome. The real incidence of MCRCC using the new diagnostic criteria is yet unclear. Large scale study is therefore needed to further identify the characteristics of MCRCC.

Von Hippel-Lindau (VHL) disease is the most common type of hereditary renal cell carcinoma in urology. The affected members in VHL disease families are at risk for developing tumors in various organs such as central nervous system, kidney, eye, and ear beginning from various ages, sometimes leading to the difficulties in recognition of this tumor syndrome. Currently, this tumor syndrome is becoming widely known by Chinese urologists. Many cases have been reported in China, but only a few reports have been found in the literature to summarize the clinical and molecular characteristics in Chinese VHL patients. Editorial CommentUrologyVol. 83Issue 3PreviewPatients with Von Hippel-Lindau (VHL) disease are at risk for the development of tumors in a number of locations, including the kidneys (clear cell renal cell carcinoma), adrenals (pheochromocytomas), central nervous system (hemangioblastomas), eyes (retinal angiomas), pancreas (pancreatic neuroendocrine tumors), ears (endolymphatic sac tumors), and epididymis (cystadenomas). Although the gene for this autosomal dominant inherited renal cancer disorder was identified in 1993, we still do not know why patients develop tumors in some organs and not others. Full-Text PDF

Objective: The coiled-coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. Here, we first reported the oncogenic roles of coiled-coil domain-containing protein 34 (CCDC34), and investigated its biological functions in bladder carcinogenesis.

You have accessJournal of UrologyKidney Cancer: Evaluation & Staging (II)1 Apr 2013739 CLINICAL CHARACTERISTICS OF VON HIPPEL-LINDAU DISEASE IN CHINESE PATIENTS Kan Gong, Pengjie Wu, Ning Zhang, Xi Wang, Xianghui Ning, Teng Li, and Dingfang Bu Kan GongKan Gong Beijing, China, People's Republic of More articles by this author , Pengjie WuPengjie Wu Beijing, China, People's Republic of More articles by this author , Ning ZhangNing Zhang Beijing, China, People's Republic of More articles by this author , Xi WangXi Wang Beijing, China, People's Republic of More articles by this author , Xianghui NingXianghui Ning Beijing, China, People's Republic of More articles by this author , Teng LiTeng Li Beijing, China, People's Republic of More articles by this author , and Dingfang BuDingfang Bu Beijing, China, People's Republic of More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.302AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES von Hippel-Lindau (VHL) disease is the most common hereditary renal cell carcinoma. It is an autosomal dominant familial cancer syndrome caused by VHL gene mutation. Here we were to study the clinical characteristics of VHL disease in China. METHODS From July 2009 to October 2012, all patients diagnosed with VHL disease based on the clinical diagnosis criteria were tested for VHL germline mutations as well their relatives. PCR-direct sequencing was used to detect intragenic mutation, and universal primer quantitative fluorescent multiplex PCR (UPQFM-PCR) was used to detect VHL large deletion. RESULTS All the 36 patients clinically diagnosed with VHL disease had VHL mutation. PCR-direct sequencing detected 28 (77.8%, 28/36) probands with germline mutations. UPQFM-PCR found 8 (22.2%, 8/36) large deletions. Remarkably, there were 52.8% (19/36) probands without family history in Chinese VHL disease families. CONCLUSIONS The incidence of VHL large deletions was up to 22.2%. So we should detect VHL large deletions as a routine to improve the ratio of correct diagnosis. Compared with NIH reports, the prevalence rate of probands without family history in China was much higher than Western and Japan (20%∼23%), suggesting high frequency of sporadic (de novo) mutations in China. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e304 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.Metrics Author Information Kan Gong Beijing, China, People's Republic of More articles by this author Pengjie Wu Beijing, China, People's Republic of More articles by this author Ning Zhang Beijing, China, People's Republic of More articles by this author Xi Wang Beijing, China, People's Republic of More articles by this author Xianghui Ning Beijing, China, People's Republic of More articles by this author Teng Li Beijing, China, People's Republic of More articles by this author Dingfang Bu Beijing, China, People's Republic of More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging II1 Apr 2017MP67-01 TELOMERE LENGTH AND GENETIC ANTICIPATION IN A LARGE COHORT OF CHINESE VON HIPPLE-LINDAU DISEASE Jiangyi Wang, Shuanghe Peng, Xianghui Ning, Teng Li, Jiayuan Liu, Shengjie Liu, and Kan Gong Jiangyi WangJiangyi Wang More articles by this author , Shuanghe PengShuanghe Peng More articles by this author , Xianghui NingXianghui Ning More articles by this author , Teng LiTeng Li More articles by this author , Jiayuan LiuJiayuan Liu More articles by this author , Shengjie LiuShengjie Liu More articles by this author , and Kan GongKan Gong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2037AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES von Hipple-Lindau(VHL) disease is an autosomal dominant familial cancer syndrome with a birth incidence of around 1/36000. Renal cell carcinoma(RCC) occurs in 35% of VHL patients, and is one of the main death causes. In order to describe the genetic characteristics of Chinese VHL patients, we have evaluated the telomere length and genetic anticipation in a large cohort of Chinese von Hipple-Lindau disease. METHODS We recruited 140 patients from 70 families with VHL disease and 51 normal controls. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Genomic DNA was extracted from peripheral blood and age-adjusted relative telomere length(aRTL) was measured with qRT-PCR method. 101 parent-child pairs were analysed for genetic anticipation by paired t test. RESULTS The mean onset age in our cohort was 29.5±11.6 years, and RCC occurred in 48.6%(68/140) VHL patients. Onset age was 16.8 years earlier for child than parent in the parent-child pairs(p<0.001). Patients in the next generation had younger onset age with shorter age-adjusted relative telomere length (p=0.018) in the 27 parent-child pairs. In addition, age-adjusted relative telomere length was shorter in the 140 VHL patients than in the normal controls(p=0.038). CONCLUSIONS This study provide evidence that telomere shortening is associated with genetic anticipation in a large Chinese cohort of VHL disease, suggesting that it might be a mechanism for pathogenesis of VHL-associated tumors. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e870 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jiangyi Wang More articles by this author Shuanghe Peng More articles by this author Xianghui Ning More articles by this author Teng Li More articles by this author Jiayuan Liu More articles by this author Shengjie Liu More articles by this author Kan Gong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) I1 Apr 2017PD04-07 HIGHER PD-L1 MRNA LEVEL IN CLEAR CELL RENAL CELL CARCINOMAS IS ASSOCIATED WITH A FAVORABLE OUTCOME Xianghui Ning, Yanqing Gong, Shiming He, Teng Li, Jiangyi Wang, Shuanghe Peng, Jinchao Chen, Jiayuan Liu, Nienie Qi, Yinglu Guo, and Kan Gong Xianghui NingXianghui Ning More articles by this author , Yanqing GongYanqing Gong More articles by this author , Shiming HeShiming He More articles by this author , Teng LiTeng Li More articles by this author , Jiangyi WangJiangyi Wang More articles by this author , Shuanghe PengShuanghe Peng More articles by this author , Jinchao ChenJinchao Chen More articles by this author , Jiayuan LiuJiayuan Liu More articles by this author , Nienie QiNienie Qi More articles by this author , Yinglu GuoYinglu Guo More articles by this author , and Kan GongKan Gong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.226AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Renal cell carcinoma (RCC) is one of the most common urological tumors. The role of programmed cell death 1 ligand 1 (PD-L1) in RCCs in predicting outcome of the patients is yet unclear. METHODS We analyzed the clinical and RNA-seq data of 522 kidney clear cell cancer (KIRC), 259 kidney papillary cell carcinoma (KIRP) and 66 kidney chromophobe (KICH) patients from The Cancer Genome Atlas (TCGA) database. RESULTS In KIRC patients with high PD-L1 mRNA level and low PD-L1 mRNA level in tumors, the median overall survival periods were 45.0 and 37.1 months respectively (p=0.002). Multivariate Cox regression tests found that PD-L1 mRNA level in tumor was an independent predictor for overall survival status in KIRC patients (HR=0.7, 95% CI 0.5-0.9, p=0.007). However, no significant difference in overall survival status was found between high and low PD-L1 groups in KIRP and KICH cohorts.Gene-set enrichment analysis on the data from databases of TCGA and GSE53757 dataset in GEO showed that several pathways relating to immunological functions were activated in KIRCs with high PD-L1 mRNA expression, and glycolysis and epithelial-mesenchymal transition pathways relating to tumor progression and metastasis were up-regulated in KIRCs with low PD-L1 mRNA level. CONCLUSIONS In conclusion, higher PD-L1 mRNA level in KIRC tissues was associated with a favorable outcome due to the higher immunological responses in tumor tissues. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e65 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Xianghui Ning More articles by this author Yanqing Gong More articles by this author Shiming He More articles by this author Teng Li More articles by this author Jiangyi Wang More articles by this author Shuanghe Peng More articles by this author Jinchao Chen More articles by this author Jiayuan Liu More articles by this author Nienie Qi More articles by this author Yinglu Guo More articles by this author Kan Gong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging II1 Apr 2017MP67-19 THE NUCLEAR GRADE AND PROGNOSIS ARE UNRELATED TO THE TNM STAGE IN MULTILOCULAR CYSTIC RENAL CELL NEOPLASM OF LOW MALIGNANT POTENTIAL Teng Li, Kan Gong, Xianghui Ning, Shuanghe Peng, Jiangyi Wang, Qun He, and Xinyu Yang Teng LiTeng Li More articles by this author , Kan GongKan Gong More articles by this author , Xianghui NingXianghui Ning More articles by this author , Shuanghe PengShuanghe Peng More articles by this author , Jiangyi WangJiangyi Wang More articles by this author , Qun HeQun He More articles by this author , and Xinyu YangXinyu Yang More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2055AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Multilocular cystic clear cell renal cell neoplasm of low malignant potential or multilocular cystic renal cell carcinoma (MCRCC) is a rare distinct subtype of clear cell renal cell carcinoma (RCC). As a rare subtype of renal cell carcinoma, this disease was mostly reported in literature as small cases series, some features about this disease remains unclear, an unresolved issue is whether this disease should be staged as other types of RCCs due to its low nuclear grade and minimal tumor burden. The present study aimed to characterize the clinical and pathologic features of MCRCC. METHODS From January 2006 to December 2014, 76 cases were identified as MCRCC among 4345 patients with RCC at our institution. Their clinical and characteristics, surgical management, pathologic features, and outcomes were retrospectively reviewed. RESULTS The incidence of MCRCC in our patients with RCC was 1.7%. The mean age at diagnosis was 46.7±10.5 years (range,18 to 80 years). Most cases showed no symptoms. Nuclear grade was unrelated to the TNM stage (P=0.451). Of these 76 patients, 66 (86.8%) were followed up for a median of 52 months, and no tumor recurrence or metastasis was found, no differences were found in the prognosis of different TNM groups. CONCLUSIONS The incidence of MCRCC in patients with RCC is low. The nuclear grade and prognosis of MCRCC cases was unrelated to the TNM stage, suggesting that the current stage criteria might not suitable for this lesion. Patients with MCRCC have an excellent prognosis; thus, the follow-up interval after surgery can be longer to minimize unnecessary examinations. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e878-e879 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Teng Li More articles by this author Kan Gong More articles by this author Xianghui Ning More articles by this author Shuanghe Peng More articles by this author Jiangyi Wang More articles by this author Qun He More articles by this author Xinyu Yang More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyKidney Cancer: Epidemiology & Evaluation/Staging III1 Apr 2017PD52-10 SHORTER TELOMERE LENGTH INCREASES AGE-RELATED TUMOR RISKS IN CHINESE VON HIPPLE-LINDAU DISEASE Jiangyi Wang, Shuanghe Peng, Xianghui Ning, Teng Li, Jiayuan Liu, Shengjie Liu, and Kan Gong Jiangyi WangJiangyi Wang More articles by this author , Shuanghe PengShuanghe Peng More articles by this author , Xianghui NingXianghui Ning More articles by this author , Teng LiTeng Li More articles by this author , Jiayuan LiuJiayuan Liu More articles by this author , Shengjie LiuShengjie Liu More articles by this author , and Kan GongKan Gong More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2198AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Von Hipple-Lindau(VHL) disease is a rare autosomal dominant familial cancer syndrome with age relatived cancer onset in patients' life. The five common tumors are central nervous system (CNS) hemangioblastoma, renal cell carcinoma(RCC) ,retinal angioma(RA), pancreatic cyst and tumor(PCT), and pheochromocytoma(Pheo). Until now, no reliable markers are found to predict the age-related tumor risks in VHL patiens. The present study has evaluated the influence of peripheral leukocyte telomere length on age-related tumor risks in a large group of VHL patients. METHODS Genomic DNA was extracted from peripheral blood of 187 VHL patients. Tumor onset age was defined as the age when any symptom or imaging sign of the tumor first occurred. Age-related risks of the five tumors were evaluated using Kaplan-Meier plot and Cox regression model. Relative telomere length(RTL) was measured with qRT-PCR method. RESULTS The main death-causing tumor CNS hemangioblastoma occurred in 53.5%(100/187) VHL patients in our study, and the mean onset age was 30.2±11.3 years old. In the shorter RTL group(RTL<0.44), the first tumor onset age was 7.7 years earlier than the longer one(25.2±8.6y vs 32.9±12.3y, p<0.001). The shorter RTL group displayed a statistically higher age-related risks than the longer RTL group for CNS(HR1.99, p=0.001), RCC(2.02, p=0.0030), PCT(2.11, p<0.001) and Pheo(3.13, p=0.005). CONCLUSIONS We for the first time propose that peripheral leukocyte telomere length may be associated with risks of VHL-related tumors, which may be helpful for establishing personalized surveillance plan for VHL patients and for further understanding the pathogenesis of VHL disease. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e993 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jiangyi Wang More articles by this author Shuanghe Peng More articles by this author Xianghui Ning More articles by this author Teng Li More articles by this author Jiayuan Liu More articles by this author Shengjie Liu More articles by this author Kan Gong More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

paired metastatic tumors, and 8 paired normal kidney samples by immunohistochemistry.RESULTS: NF2 mutations are enriched in higher grade (>pT3, pT4) and metastatic tumors compared to low grade or non-metastatic tumors (20-30% vs. 1.5%), and are associated with a decreased disease-free survival.Cell lines derived from metastatic RCC have lower NF2 expression than cell lines derived from local tumors, more importantly, MERLIN protein levels are decreased or undetectable by Western blot or IHC in metastatic derived cell lines.The metastatic lines Caki1 and ACHN have increased metastatic potential as measured by increased colony formation.MERLIN was absent in a tumor with sarcomatoid differentiation but was present in all 8 metastatic samples.CONCLUSIONS: These results support a potential intriguing role for MERLIN loss of function in the clinically-relevant phenotypic transition from localized to invasive RCC.The model system described here will provide a crucial framework for testing MERLIN 0 s influence on invasiveness through knockdown and rescue of MERLIN activity in appropriate RCC cell lines.

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II1 Apr 2017MP48-05 IDENTIFICATION OF CCDC34 AS AN ONCOGENE IN BLADDER CANCER AND ITS FUNCTION DURING BLADDER CARCINOGENESIS Yanqing Gong, Xianghui Ning, Xinyu Yang, Jian Lin, Xuesong Li, and Yinglu Guo Yanqing GongYanqing Gong More articles by this author , Xianghui NingXianghui Ning More articles by this author , Xinyu YangXinyu Yang More articles by this author , Jian LinJian Lin More articles by this author , Xuesong LiXuesong Li More articles by this author , and Yinglu GuoYinglu Guo More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1486AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The coiled coil is a superhelical structural protein motif involved in a diverse array of biological functions, and the abnormal expression of the coiled-coil domain containing proteins has a direct link with the phenotype of tumor cell migration, invasion and metastasis. Here, we first reported the oncogenic roles of Coiled-coil domain-containing protein 34 (CCDC34), and investigated its biological functions in bladder carcinogenesis. METHODS Immunohistochemical staining and western blot were used to detect CCDC34 expression in bladder cancers specimens and cell lines. Lentivirus-mediated RNA interference and overexpression strategies were used to assess the effects of CCDC34 expression on various malignant phenotypes. The biological functions of CCDC34 knockdown on cells (T24 and 5637) were investigated by examining cell proliferation using a high content screening assay (HCS), BrdU incorporation assay and colony formation assay, cell migration by in vitro wound healing assay, cell invasion by Transwell invasion assay, as well as cell cycle distribution and apoptosis by flow cytometry. The expressions of Bcl-2, c-Raf, c-Jun, N-cadherin and E-cadherin as well as the phosphorylation of MEK, ERK1/2 and AKT were also measured using Western blot. We further investigated the effect of therapeutic siRNA targeting CCDC34 on T24 xenograft tumor growth in nude mice. RESULTS CCDC34 was up-regulated in human bladder cancer tissues and cell lines. CCDC34 was distributed mainly in the cytoplasm, and its expression was closely correlated with histological type, tumor grade and pathologic stage (n=87, P<0.05). Besides, Western blot confirmed that CCDC34 was expressed at higher level in human bladder cancer tissues compared with their paraneoplastic normal bladder tissues (n=18, P=0.012). Knockdown of CCDC34 significantly suppressed bladder cancer cells proliferation, migration and invasion (P<0.01), and induced cell cycle arrest at G2/M phase and increased apoptosis in vitro (P<0.01). Moreover, CCDC34 knockdown decreased phosphorylation of MEK, ERK1/2 and AKT, and the expressions of c-Raf, c-Jun and Bcl-2; while CCDC34 overexpression in T24 cells promoted cell migration and invasion with increased EMT, and treatment with MAPK/ERK1/2 and PI3K/AKT inhibitors blocked the phosphorylation of ERK1/2 and AKT, respectively. In addition, knockdown of CCDC34 suppressed bladder cancer cell growth in nude mice. CONCLUSIONS Our findings revealed for the first time a potential oncogenic role for CCDC34 in bladder carcinoma pathogenesis, and activation of MAPK/ERK1/2 and PI3K/AKT signaling pathways was required for CCDC34 modulation of bladder cancer cell proliferation, migration and invasion. CCDC34 may serve as a biomarker or even a therapeutic target for bladder carcinoma. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e638 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Yanqing Gong More articles by this author Xianghui Ning More articles by this author Xinyu Yang More articles by this author Jian Lin More articles by this author Xuesong Li More articles by this author Yinglu Guo More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Mutation or inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene is an early event in the pathogenesis of clear cell renal cell carcinomas (RCCs) and is common in both hereditary and nonhereditary forms.

Abstract Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p=0.834) and between first-born patients and the other siblings (p=0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology I (MP16)1 Apr 2019MP16-03 DOWNREGULATION AND FREQUENT PROMOTER HYPERMETHYLATION OF CLDN7 CORRELATE WITH TUMOR PROGRESSION AND POOR PROGNOSIS IN HUMAN CLEAR CELL RENAL CELL CARCINOMA Yanqing Gong*, Yifan Li, Xianghui Ning, Xuesong Li, Kan Gong, and Liqun Zhou Yanqing Gong*Yanqing Gong* More articles by this author , Yifan LiYifan Li More articles by this author , Xianghui NingXianghui Ning More articles by this author , Xuesong LiXuesong Li More articles by this author , Kan GongKan Gong More articles by this author , and Liqun ZhouLiqun Zhou More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000555339.89148.a4AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Metastasis is the primary cause of death in renal cell carcinoma (RCC). Loss of cell-to-cell adhesion, including tight junctions (TJs) is the initial step in the process of metastasis. Claudin-7 (CLDN7) is a major component of TJs. However, the clinical significance and its regulation of kidney tumorigenesis remain poorly understood. METHODS: Total 120 fresh ccRCC specimen and 144 primary RCC and adjacent non-malignant renal paraffin specimen were obtained from Peking University First Hospital. Expression of CLDN7 in ccRCC were determined by bioinformatic data mining, qRT-PCR, Western blot and immunostaining. The clinical significance of CLDN7 expression and promoter methylation status was analyzed in ccRCC patients. The methylation specific-PCR, bisulfite genomic sequencing and demethylation analysis of CLDN7 were performed in ccRCC. Biological functions of lentivirus-mediated CLDN7 overexpression on ccRCC cells proliferation, migration and invasion were investigated. Mice experiments were performed to confirm effects of CLDN7 on tumor growth and metastasis in vivo. Molecular mechanism of CLDN7 function was investigated by gene-set enrichment analysis (GSEA) and high-throughput cDNA sequencing (RNA-Seq) and confirmed by qRT-PCR, western blot and immunostaining in vitro and in vivo. RESULTS: CLDN7 was frequently downregulated via hypermethylation of its promoter in ccRCC. CLDN7 can help predict aggressive tumor status and poor prognosis in ccRCC patients. Hypermethylation of CLDN7 promoter was related to advanced ccRCC and poor prognosis. Moreover, overexpression of CLDN7 induced cell apoptosis, suppressed proliferation, migration and invasion abilities of ccRCC cells both in vitro and in vivo. In addition, GSEA and RNA-Seq results showed high expression of CLDN7 had negative effect in cancer-associated signaling pathways and (epithelial-mesenchymal transition) EMT-related pathways, and results were validated by qRT-PCR, Western blot and immunostaining. CONCLUSIONS: We have demonstrated a previously undescribed role of CLDN7 as a ccRCC suppressor and suggest that loss of CLDN7 potentiates EMT and tumor progression. CLDN7 may serve as a functional tumor suppressor in tumor progression and a potential biomarker and target in patients with ccRCC. Source of Funding: None Beijing, China, People's Republic of; Henan, China, People's, Republic of; Beijing, China, People's Republic of© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e206-e206 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yanqing Gong* More articles by this author Yifan Li More articles by this author Xianghui Ning More articles by this author Xuesong Li More articles by this author Kan Gong More articles by this author Liqun Zhou More articles by this author Expand All Advertisement PDF downloadLoading ...

Additional file 1: Supplementary table 1. Demographical information of the cohorts. Supplementary table 2. Association results of SNPs in CTLA4-ICOS region and SLE susceptibility (1). Supplementary Table 3. Synthesized sequences for subcloning into pGL3-promoter. Supplementary Table 4. The sequences of the synthetic double-stranded oligonucleotides for protein mass spectrometry and EMSA. Supplementary table 5. Regulatory chromatin states from DNAse and histone ChIP-Seq (Roadmap Epigenomics Consortium, 2015) (2). Supplementary table 6. Single-Tissue eQTLs for rs17268364. Supplementary Figure 1. The correlation between mRNA expression of CTLA4 and rs17268364 genotypes. A. Healthy controls B. systemic lupus erythematosus patients without renal impairment. Supplementary Figure 2. The correlation between mRNA expression of ICOS and rs17268364 genotypes in SLE patients without renal impairment (A), lupus nephritis patients (B), and SLE patients (C). Supplementary Figure 3. Linkage disequilibrium (LD) heatmap of the 24 identified SLE-associated SNPs. The Linkage disequilibrium (LD) heatmap of the 24 identified SLE-associated SNPs was generated using genotype data of 103 Chinese Han Beijing individuals from 1000 genome project. The degrees of LD were estimated by CI method using Haploview4.2 (Cambridge, MA, USA) and a standard color scheme (D’/LOD) is used to display the LD pattern.