Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Andrew V Biankin, Nicola Waddell, Karin S Kassahn, Marie-Claude Gingras, Lakshmi B Muthuswamy, Amber L Johns, David K Miller, Peter J Wilson, Ann-Marie Patch, Jianmin Wu, David K Chang, Mark J Cowley, Brooke B Gardiner, Sarah Song, Ivon Harliwong, Senel Idrisoglu, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Shivangi WaniMilena 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, Katia Nones, Angelika Christ, Tim Bruxner, Nicole Cloonan, Gabriel Kolle, Felicity Newell, Mark Pinese, R Scott Mead, Jeremy L Humphris, Warren Kaplan, Marc D Jones, Emily K Colvin, Adnan M Nagrial, Emily S Humphrey, Angela Chou, Vanessa T Chin, Lorraine A Chantrill, Amanda Mawson, Jaswinder Samra, James G Kench, Jessica A Lovell, Roger John Daly, Neil D Merrett, Christopher Toon, Krishna Epari, Nam Q Nguyen, Andrew Barbour, Nikolajs Zeps, Nipun Kakkar, Fengmei Zhao, Yuan Qing 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 R Lewis, Huyen Dinh, Christian J 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, Particia A 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, Giamopaolo Tortora, Margaret A Tempero, Karen M Mann, Nancy A Jenkins, Pedro A Perez-Mancera, David J Adams, David A Largaespada, Lodewyk F Wessels, Alistair G Rust, Lincoln D 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 D McPherson, Richard A Gibbs, Sean Grimmond

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1198 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)399 - 405
Number of pages7
JournalNature
Volume49
Issue number7424
DOIs
Publication statusPublished - 2012
Externally publishedYes

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