Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

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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Data deposits

BAM files and associated metadata in XML format have been uploaded to the European Genome-phenome Archive (EGA; http://www.ebi.ac.uk/ega) under accession numbers GAS00001000154 and EGAS00001000343. Additional sequence data is located at dbGAP accession number phs000516.v1.p1.

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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 and G. Hammond for central coordination of 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 Economic Development and Innovation; Canada Foundation for 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.

Author information

  1. Robert L. Sutherland: Deceased.

Authors and Affiliations

  1. The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia., Andrew V. Biankin, Amber L. Johns, Jianmin Wu, David K. Chang, Mark J. Cowley, Marina Pajic, Christopher J. Scarlett, Anthony J. Gill, Andreia V. Pinho, Ilse Rooman, 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, James G. Kench, Jessica A. Lovell, Roger J. Daly, Christopher Toon, Elizabeth A. Musgrove & Robert L. Sutherland
  2. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia., Andrew V. Biankin, David K. Chang & Neil D. Merrett
  3. South Western Sydney Clinical School, Faculty of Medicine, University of NewSouth Wales, Liverpool, 2170, NewSouth Wales, Australia Andrew V. Biankin & David K. Chang
  4. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, 4072, Queensland, Australia Nicola Waddell, Karin S. Kassahn, David K. Miller, Peter J. Wilson, Ann-Marie Patch, Brooke B. Gardiner, 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 & Sean M. Grimmond
  5. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA., Marie-Claude Gingras, Nipun Kakkar, Fengmei Zhao, Yuan Qing Wu, Min Wang, Donna M. Muzny, Jeffrey G. Reid, Jennifer Drummond, Kyle Chang, Yi Han, Lora R. Lewis, Huyen Dinh, Christian J. Buhay, David A. Wheeler & Richard A. Gibbs
  6. Michael E. DeBakey Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA., Marie-Claude Gingras, William E. Fisher & Sally E. Hodges
  7. Ontario Institute for Cancer Research, Toronto, M5G 0A3, Canada Lakshmi B. Muthuswamy, 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, Nicole Onetto, Lincoln D. Stein, Thomas J. Hudson & John D. McPherson
  8. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, 2258, New South Wales, Australia Christopher J. Scarlett
  9. Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, 2065, New South Wales, Australia Anthony J. Gill & Jaswinder S. Samra
  10. University of Sydney, Sydney, 2006, New South Wales, Australia Anthony J. Gill & James G. Kench
  11. Life Technologies, Brisbane, 4000, Queensland, Australia Gabriel Kolle
  12. Department of Anatomical Pathology, Sydpath, St Vincent’s Hospital, Sydney, 2010, New South Wales, Australia R. Scott Mead & Angela Chou
  13. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, 2065, New South Wales, Australia Jaswinder S. Samra
  14. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, 2050, New South Wales, Australia James G. Kench
  15. School of Medicine, University of Western Sydney, Penrith, 2175, New South Wales, Australia Neil D. Merrett
  16. Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia., Krishna Epari
  17. Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia., Nam Q. Nguyen
  18. Department of Surgery, The University of Queensland, Princess Alexandra Hospital, Ipswich Road, Woollongabba, Queensland 4102, Australia., Andrew Barbour
  19. School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Road, Subiaco, Western Australia 6008, USA., Nikolajs Zeps
  20. The Elkins Pancreas Center atBaylor College ofMedicine, 6620 Main Street, Suite 1450, Houston, Texas 77030, USA., William E. Fisher & Sally E. Hodges
  21. David Geffen School of Medicine at UCLA, Los Angeles, 90024, Callfornia, USA F. Charles Brunicardi
  22. University Health Network, Toronto, M5G2C4, Canada Stefano Serra, Ming-Sound Tsao, Patricia A. Shaw & Steven Gallinger
  23. Mayo Clinic, Rochester, 55905, Minnesota, USA Debabrata Mukhopadhyay & Gloria M. Petersen
  24. Mount Sinai Hospital, Toronto, M5G 1X5, Canada Steven Gallinger
  25. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard A. Morgan & James R. Eshleman
  26. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA Richard D. Schulick & Christopher L. Wolfgang
  27. ARC-NET center for applied research on cancer, University and Hospital Trust of Verona, Verona, 37134, Italy Rita T. Lawlor, Vincenzo Corbo & Aldo Scarpa
  28. Department of Pathology and Diagnostics, University of Veron, Verona, 37134, Italy Paola Capelli, Maria Scardoni & Aldo Scarpa
  29. Department of Surgery and Oncology, University and Hospital Trust of Verona, Verona, 37134, Italy Giampaolo Tortora
  30. Division of Hematology and Oncology, University of California, San Francisco, 94115, USA Margaret A. Tempero
  31. Cancer Research Program, The Methodist Hospital Research Institute, 6670 Bertner Avenue, Houston, Texas 77030, USA., Karen M. Mann, Nancy A. Jenkins & Neal G. Copeland
  32. and Department of Oncology, Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Robinson Way, CB2 0RE, Cambridge, UK Pedro A. Perez-Mancera & David A. Tuveson
  33. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, CB10 1HH, UK David J. Adams & Alistair G. Rust
  34. Masonic Cancer Center, University of Minnesota, Minneapolis, 55455, Minnesota, USA David A. Largaespada
  35. Bioinformatics and Statistics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands., Lodewyk F. A. Wessels
  36. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, New South Wales, 2010, Australia Elizabeth A. Musgrove & Robert L. Sutherland
  37. The Kinghorn Cancer Centre, Cancer Research Program, Garvan Institute of Medical Research, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia., 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
  38. Queensland Center for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, 4072, Queensland, Australia 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
  39. Royal North Shore Hospital, Westbourne Street,, St Leonards, 2065, New South Wales, Australia Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski & Christopher Toon
  40. Bankstown Hospital, Eldridge Road,, Bankstown, 2200, New South Wales, Australia Andrew V. Biankin, Ray Asghari, Neil D. Merrett, David K. Chang, Darren A. Pavey & Amitabha Das
  41. Liverpool Hospital, Elizabeth Street, Liverpool, 2170, New South Wales, Australia Peter H. Cosman, Kasim Ismail & Chelsie O’Connor
  42. Westmead Hospital, Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia., Vincent W. Lam, Duncan McLeod, Henry C. Pleass, Arthur Richardson & Virginia James
  43. Royal Prince Alfred Hospital, Missenden Road, Camperdown, New South Wales 2050, Australia., James G. Kench, Caroline L. Cooper, David Joseph, Charbel Sandroussi, Michael Crawford & James Gallagher
  44. Fremantle Hospital, Alma Street, Fremantle, Western Australia 6959, Australia., Michael Texler, Cindy Forrest, Andrew Laycock, Krishna P. Epari, Mo Ballal, David R. Fletcher & Sanjay Mukhedkar
  45. Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, 6009, Western Australia, Australia Nigel A. Spry, Bastiaan DeBoer & Ming Chai
  46. St John of God Healthcare, 12 Salvado Road, Subiaco, Western Australia 6008, Australia., Nikolajs Zeps, Maria Beilin & Kynan Feeney
  47. Royal Adelaide Hospital, North Terrace, Adelaide, 5000, South Australia, Australia Nam Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan & Tamara Debrencini
  48. Flinders Medical Centre, Flinders Drive, Bedford Park, 5042, South Australia, Australia John Chen, Mark E. Brooke-Smith & Virginia Papangelis
  49. Greenslopes Private Hospital, Newdegate Street, Greenslopes, Queensland 4120, Australia., Henry Tang & Andrew P. Barbour
  50. Envoi Pathology, 1/49 Butterfield Street, Herston, Queensland 4006, Australia., Andrew D. Clouston & Patrick Martin
  51. Princess Alexandria Hospital, Cornwall Street & Ipswich Road, Woolloongabba, Queensland 4102, Australia., Thomas J. O’Rourke, Amy Chiang, Jonathan W. Fawcett, Kellee Slater, Shinn Yeung, Michael Hatzifotis & Peter Hodgkinson
  52. Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia., Christopher Christophi, Mehrdad Nikfarjam & Angela Mountain Victorian Cancer Biobank
  53. Victorian Cancer Biobank, 1 Rathdowne Street, Carlton, Victoria 3053, Australia., Angela Mountain Victorian Cancer Biobank
  54. Johns Hopkins Medical Institutes, 600 North Wolfe Street, Baltimore, Maryland 21287, USA., James R. Eshleman, Ralph H. Hruban, Anirban Maitra, Christine A. Iacobuzio-Donahue, Richard D. Schulick, Christopher L. Wolfgang, Richard A. Morgan & Mary B. Hodgin
  55. ARC-NET Center for Applied Research on Cancer, University of Verona, Via dell’Artigliere, 19 37129 Verona 37134, Italy., Aldo Scarpa, Rita T. Lawlor, Paola Capelli, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni, Paolo Pederzoli, Giampaolo Tortora & Claudio Bassi
  56. University of California, San Francisco, 1600 Divisadero Street, San Francisco, California 94115, USA., Margaret A. Tempero
  1. Andrew V. Biankin