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, J. Lynn Fink, 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, Venessa T. Chin, Lorraine A. Chantrill, Amanda Mawson, Jaswinder S. Samra, James G. Kench, Jessica A. Lovell, Roger J. 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, Patricia 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, Giampaolo Tortora, Margaret A. Tempero, Karen M. Mann, Nancy A. Jenkins, Pedro A. Perez-Mancera, David J. Adams, David A. Largaespada, Lodewyk F A 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 M. Grimmond

Research output: Contribution to journalArticlepeer-review

1170 Scopus citations

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 (US)
Pages (from-to)399-405
Number of pages7
JournalNature
Volume491
Issue number7424
DOIs
StatePublished - Nov 15 2012

Bibliographical note

Funding Information:
Acknowledgements This paper is dedicated to Robert L. Sutherland who died on 10 October 2012 of pancreatic cancer. We would like to thank C. Axford, D. Gwynne, M.-A. Brancato,S.Rowe, M. Thomas, S.Simpson andG.Hammondfor central coordinationof the Australian Pancreatic Cancer Genome Initiative, data management and quality control; M. Martyn-Smith, L. Braatvedt, H. Tang, V. Papangelis and M. Beilin for biospecimen acquisition; and W. Waterson, J. Shepperd, E. Campbell and E. Glasov for their efforts at the Queensland Centre for Medical Genomics. We also thank M. B. Hodgin, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University, and J. Lau, M. Karaus, K. Rabe, L. Zhang and T. Smyrk at the Mayo Clinic. We acknowledge the following funding support: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601, 535914); Australian Government: Department of Innovation, Industry, Science, Research and Tertiary Education (DIISRTE); Australian Cancer Research Foundation (ACRF); Queensland Government (NIRAP); University of Queensland; Cancer Council NSW (SRP06-01; ICGC09-01; SRP11-01); Cancer Institute NSW (06/ECF/1-24, 09/CDF/2-40, 07/CDF/ 1-03, 10/CRF/1-01, 08/RSA/1-15, 07/CDF/1-28, 10/CDF/2-26,10/FRL/2-03, 06/ RSA/1-05, 09/RIG/1-02, 10/TPG/1-04, 11/REG/1-10, 11/CDF/3-26); Garvan Institute of Medical Research; Avner Nahmani Pancreatic Cancer Research Foundation; R.T. Hall Trust; Petre Foundation; Jane Hemstritch in memory of Philip Hemstritch; Gastroenterological Society of Australia (GESA); American Association for Cancer Research (AACR) Landon Foundation – INNOVATOR Award; Royal Australasian College of Surgeons (RACS); Royal Australasian College of Physicians (RACP); Royal College of Pathologists of Australasia (RCPA); HGSC-BCM: NHGRI U54 HG003273; CPRIT grant RP101353-P7 (Tumor Banking for Genomic Research and Clinical Translation Site 1); The Ontario Institute for Cancer Research; The Ontario Ministry of EconomicDevelopmentandInnovation;CanadaFoundationfor Innovation;Pancreatic Cancer Genetic Epidemiology Consortium, NIH grant R01 CA97075; The Agency for Science, Technology, and Research (Singapore); University of Verona and Italian Ministry of University (FIRB RBAP10AHJB), Rome, Italy; Cancer Research UK; Wellcome Trust; CPRIT (Cancer Prevention Research Institute of Texas); NIH P50CA062924 (SPORE) and P01CA134292 (PPG); The Sol Goldman Pancreatic Cancer Research Center; NCI grant P50 CA102701 (Mayo Clinic SPORE in Pancreatic Cancer) and NCI grant R01 CA97075 (Pancreatic Cancer Genetic Epidemiology Consortium); NIH SPORE grant 2P50CA101955 (UMN/UAB), and AIRC (Associazione Italiana Ricerca sul Cancro) 5xmille grant 12182, Italy.

Fingerprint Dive into the research topics of 'Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes'. Together they form a unique fingerprint.

Cite this