DOI: 10.1038/nature11547

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Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Andrew V. Biankin,Nicola Waddell,Karin S. Kassahn,Marie Claude Gingras,Lakshmi Muthuswamy,Amber Johns,David Miller,Peter J. Wilson,Ann Marie Patch,Jianmin Wu,David K. Chang,Mark J. Cowley,Brooke Gardiner,Sarah Song,Ivon Harliwong,Senel Idrisoglu,Craig Nourse,Ehsan Nourbakhsh,Suzanne Manning,Shivangi Wani,Milena Gongora,Marina Pajic,Christopher J. Scarlett,Anthony J. Gill,Andreia V. Pinho,Ilse Rooman,Matthew Anderson,Oliver Holmes,Conrad Leonard,Darrin Taylor,Scott Wood,Qinying Xu,Kátia Nones,J. Lynn Fink,Angelika N. Christ,Timothy J. C. Bruxner,Nicole Cloonan,Gabriel Kolle,Felicity Newell,Mark Pinese,R. Scott Mead,Jeremy L. Humphris,Warren Kaplan,Marc D. Jones,Emily K. Colvin,Adnan Nagrial,Emily S. Humphrey,Angela Chou,Venessa Chin,Lorraine A. Chantrill,Amanda Mawson,Jaswinder S. Samra,James G. Kench,Jessica A. Lovell,Roger J. Daly,Neil D. Merrett,Christopher W. Toon,Krishna Epari,Nam Q. Nguyen,Andrew P. Barbour,Nikolajs Zeps,Nipun Kakkar,Fengmei Zhao,Yuan Wu,Min Wang,Donna M. Muzny,William E. Fisher,F. Charles Brunicardi,Sally E. Hodges,Jeffrey G. Reid,Jennifer Drummond,Kyle Chang,Yi Han,Lora Lewis,Huyen Dinh,Christian Buhay,Timothy Beck,Lee Timms,Michelle Sam,Kimberly Begley,Andrew Brown,Deepa Pai,Ami Panchal,Nicholas Buchner,Richard de Borja,Robert E. Denroche,Christina K. Yung,Stefano Serra,Nicole Onetto,Debabrata Mukhopadhyay,Ming‐Sound Tsao,Patricia Shaw,Gloria M. Petersen,Steven Gallinger,Ralph H. Hruban,Anirban Maitra,Christine A. Iacobuzio‐Donahue,Richard D. Schulick,Christopher L. Wolfgang,Richard A. Morgan,Rita T. Lawlor,Paola Capelli,Vincenzo Corbo,Maria Scardoni,Giampaolo Tortora,Margaret A. Tempero,Karen Mann,Nancy A. Jenkins,Pedro A. Pérez‐Mancera,David J. Adams,David A. Largaespada,Lodewyk Wessels,Alistair G. Rust,Lincoln Stein,David A. Tuveson,Neal G. Copeland,Elizabeth A. Musgrove,Aldo Scarpa,James R. Eshleman,Thomas J. Hudson,Robert L. Sutherland,David A. Wheeler,John V. Pearson,John Douglas Mcpherson,Richard A. Gibbs,Sean M. Grimmond

Biology

KRAS

Pancreatic cancer

2012

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

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“Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes” is a paper by Andrew V. Biankin Nicola Waddell Karin S. Kassahn Marie Claude Gingras Lakshmi Muthuswamy Amber Johns David Miller Peter J. Wilson Ann Marie Patch Jianmin Wu David K. Chang Mark J. Cowley Brooke Gardiner Sarah Song Ivon Harliwong Senel Idrisoglu Craig Nourse Ehsan Nourbakhsh Suzanne Manning Shivangi Wani Milena Gongora Marina Pajic Christopher J. Scarlett Anthony J. Gill Andreia V. Pinho Ilse Rooman Matthew Anderson Oliver Holmes Conrad Leonard Darrin Taylor Scott Wood Qinying Xu Kátia Nones J. Lynn Fink Angelika N. Christ Timothy J. C. Bruxner Nicole Cloonan Gabriel Kolle Felicity Newell Mark Pinese R. Scott Mead Jeremy L. Humphris Warren Kaplan Marc D. Jones Emily K. Colvin Adnan Nagrial Emily S. Humphrey Angela Chou Venessa Chin Lorraine A. Chantrill Amanda Mawson Jaswinder S. Samra James G. Kench Jessica A. Lovell Roger J. Daly Neil D. Merrett Christopher W. Toon Krishna Epari Nam Q. Nguyen Andrew P. Barbour Nikolajs Zeps Nipun Kakkar Fengmei Zhao Yuan Wu Min Wang Donna M. Muzny William E. Fisher F. Charles Brunicardi Sally E. Hodges Jeffrey G. Reid Jennifer Drummond Kyle Chang Yi Han Lora Lewis Huyen Dinh Christian Buhay Timothy Beck Lee Timms Michelle Sam Kimberly Begley Andrew Brown Deepa Pai Ami Panchal Nicholas Buchner Richard de Borja Robert E. Denroche Christina K. Yung Stefano Serra Nicole Onetto Debabrata Mukhopadhyay Ming‐Sound Tsao Patricia Shaw Gloria M. Petersen Steven Gallinger Ralph H. Hruban Anirban Maitra Christine A. Iacobuzio‐Donahue Richard D. Schulick Christopher L. Wolfgang Richard A. Morgan Rita T. Lawlor Paola Capelli Vincenzo Corbo Maria Scardoni Giampaolo Tortora Margaret A. Tempero Karen Mann Nancy A. Jenkins Pedro A. Pérez‐Mancera David J. Adams David A. Largaespada Lodewyk Wessels Alistair G. Rust Lincoln Stein David A. Tuveson Neal G. Copeland Elizabeth A. Musgrove Aldo Scarpa James R. Eshleman Thomas J. Hudson Robert L. Sutherland David A. Wheeler John V. Pearson John Douglas Mcpherson Richard A. Gibbs Sean M. Grimmond published in 2012. It has an Open Access status of “green”. You can read and download a PDF Full Text of this paper here.