Title |
Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes
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Published in |
Nature, October 2012
|
DOI | 10.1038/nature11547 |
Pubmed ID | |
Authors |
Andrew V. Biankin, Amber L. Johns, Amanda Mawson, David K. Chang, Christopher J. Scarlett, Mary-Anne L. Brancato, Sarah J. Rowe, Skye L. Simpson, Mona Martyn-Smith, Michelle T. Thomas, Lorraine A. Chantrill, Venessa T. Chin, Angela Chou, Mark J. Cowley, Jeremy L. Humphris, Marc D. Jones, R. Scott Mead, Adnan M. Nagrial, Marina Pajic, Jessica Pettit, Mark Pinese, Ilse Rooman, Jianmin Wu, Jiang Tao, Renee DiPietro, Clare Watson, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Sean M. Grimmond, Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi Wani, Milena Gongora, Matthew Anderson, Oliver Holmes, Conrad Leonard, Darrin Taylor, Scott Wood, Qinying Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski, Christopher Toon, Andrew V. Biankin, Ray Asghari, Neil D. Merrett, David K. Chang, Darren A. Pavey, Amitabha Das, Peter H. Cosman, Kasim Ismail, Chelsie O’Connor, Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson, Virginia James, James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford, James Gallagher, Michael Texler, Cindy Forrest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher, Sanjay Mukhedkar, Nigel A. Spry, Bastiaan DeBoer, Ming Chai, Nikolajs Zeps, Maria Beilin, Kynan Feeney, Nam Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan, Tamara Debrencini, John Chen, Mark E. Brooke-Smith, Virginia Papangelis, Henry Tang, Andrew P. Barbour, Andrew D. Clouston, Patrick Martin, Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis, Peter Hodgkinson, Christopher Christophi, Mehrdad Nikfarjam, Angela Mountain Victorian Cancer Biobank, James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan, Mary B. Hodgin, Aldo Scarpa, Rita T. Lawlor, Paola Capelli, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Paolo Pederzoli, Giampaolo Tortora, Claudio Bassi, Margaret A. Tempero |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 35 | 24% |
Australia | 13 | 9% |
United Kingdom | 13 | 9% |
Canada | 6 | 4% |
Spain | 4 | 3% |
India | 3 | 2% |
Germany | 2 | 1% |
France | 2 | 1% |
South Africa | 2 | 1% |
Other | 16 | 11% |
Unknown | 50 | 34% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 89 | 61% |
Scientists | 39 | 27% |
Practitioners (doctors, other healthcare professionals) | 13 | 9% |
Science communicators (journalists, bloggers, editors) | 5 | 3% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 26 | 2% |
Germany | 5 | <1% |
Canada | 4 | <1% |
United Kingdom | 4 | <1% |
Australia | 3 | <1% |
Japan | 3 | <1% |
China | 3 | <1% |
France | 3 | <1% |
Netherlands | 2 | <1% |
Other | 10 | <1% |
Unknown | 1226 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 293 | 23% |
Researcher | 272 | 21% |
Student > Master | 98 | 8% |
Student > Bachelor | 87 | 7% |
Other | 78 | 6% |
Other | 242 | 19% |
Unknown | 219 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 334 | 26% |
Biochemistry, Genetics and Molecular Biology | 320 | 25% |
Medicine and Dentistry | 232 | 18% |
Computer Science | 25 | 2% |
Pharmacology, Toxicology and Pharmaceutical Science | 24 | 2% |
Other | 106 | 8% |
Unknown | 248 | 19% |