Whole genomes redefine the mutational landscape of pancreatic cancer (original) (raw)

Accession codes

Primary accessions

Gene Expression Omnibus

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 number EGAS00001000154. All SNP array data is available via GEO (GSE61502). For more information about Australian Pancreatic Cancer Genome Initiative, see (http://www.pancreaticcancer.net.au/apgi/collaborators).

References

  1. Vogelzang, N. J. et al. Clinical cancer advances 2011: annual report on progress against cancer from the American Society of Clinical Oncology. J. Clin. Oncol. 30, 88–109 (2012)
    PubMed Google Scholar
  2. Biankin, A. V. et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491, 399–405 (2012)
    CAS PubMed PubMed Central Google Scholar
  3. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)
    ADS CAS PubMed PubMed Central Google Scholar
  4. Harada, T. et al. Genome-wide DNA copy number analysis in pancreatic cancer using high-density single nucleotide polymorphism arrays. Oncogene 27, 1951–1960 (2008)
    CAS PubMed Google Scholar
  5. Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011)
    MathSciNet CAS PubMed PubMed Central Google Scholar
  6. Stephens, P. J. et al. Complex landscapes of somatic rearrangement in human breast cancer genomes. Nature 462, 1005–1010 (2009)
    ADS CAS PubMed PubMed Central Google Scholar
  7. Griffin, C. A. et al. Consistent chromosome abnormalities in adenocarcinoma of the pancreas. Cancer Res. 55, 2394–2399 (1995)
    CAS PubMed Google Scholar
  8. Molenaar, J. J. et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature 483, 589–593 (2012)
    ADS CAS PubMed Google Scholar
  9. Campbell, P. J. et al. The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467, 1109–1113 (2010)
    ADS CAS PubMed PubMed Central Google Scholar
  10. Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011)
    CAS PubMed Google Scholar
  11. Sultana, A. et al. Meta-analyses of chemotherapy for locally advanced and metastatic pancreatic cancer. J. Clin. Oncol. 25, 2607–2615 (2007)
    PubMed Google Scholar
  12. Ciliberto, D. et al. Role of gemcitabine-based combination therapy in the management of advanced pancreatic cancer: a meta-analysis of randomised trials. Eur. J. Cancer 49, 593–603 (2013)
    CAS PubMed Google Scholar
  13. Heinemann, V., Boeck, S., Hinke, A., Labianca, R. & Louvet, C. Meta-analysis of randomized trials: evaluation of benefit from gemcitabine-based combination chemotherapy applied in advanced pancreatic cancer. BMC Cancer 8, 82 (2008)
    PubMed PubMed Central Google Scholar
  14. Oettle, H. et al. Second-line oxaliplatin, folinic acid, and fluorouracil versus folinic acid and fluorouracil alone for gemcitabine-refractory pancreatic cancer: outcomes from the CONKO-003 Trial. J. Clin. Oncol. 32, 2423–2429 (2014)
    CAS PubMed Google Scholar
  15. Kaufman, B. et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J. Clin. Oncol. 33, 244–250 (2015)
    CAS PubMed Google Scholar
  16. International Cancer Genome Consortium et al International network of cancer genome projects. Nature 464, 993–998 (2010)
    ADS Google Scholar
  17. Popova, T. et al. Genome alteration print (GAP): a tool to visualize and mine complex cancer genomic profiles obtained by SNP arrays. Genome Biol. 10, R128 (2009)
    PubMed PubMed Central Google Scholar
  18. Song, S. et al. qpure: a tool to estimate tumor cellularity from genome-wide single-nucleotide polymorphism profiles. PLoS ONE 7, e45835 (2012)
    ADS CAS PubMed PubMed Central Google Scholar
  19. Kassahn, K. S. et al. Somatic point mutation calling in low cellularity tumors. PLoS ONE 8, e74380 (2013)
    ADS CAS PubMed PubMed Central Google Scholar
  20. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013)
    CAS PubMed PubMed Central Google Scholar
  21. Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013)
    ADS CAS PubMed PubMed Central Google Scholar
  22. Mann, K. M. et al. Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proc. Natl Acad. Sci. USA 109, 5934–5941 (2012)
    ADS CAS PubMed PubMed Central Google Scholar
  23. Berger, M. F. et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature 485, 502–506 (2012)
    ADS CAS PubMed PubMed Central Google Scholar
  24. Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 12649–12654 (2013)
    ADS CAS PubMed PubMed Central Google Scholar
  25. Korbel, J. O. & Campbell, P. J. Criteria for inference of chromothripsis in cancer genomes. Cell 152, 1226–1236 (2013)
    CAS PubMed Google Scholar
  26. Tutt, A. et al. Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification. Curr. Biol. 9, 1107–1110 (1999)
    CAS PubMed Google Scholar
  27. Jones, S. et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 324, 217 (2009)
    ADS CAS PubMed PubMed Central Google Scholar
  28. Hellebrand, H. et al. Germline mutations in the PALB2 gene are population specific and occur with low frequencies in familial breast cancer. Hum. Mutat. 32, E2176–E2188 (2011)
    CAS PubMed Google Scholar
  29. Nikkilä, J. et al. Heterozygous mutations in PALB2 cause DNA replication and damage response defects. Nature Commun. 4, 2578 (2013)
    ADS Google Scholar
  30. Nones, K. et al. Genome-wide DNA methylation patterns in pancreatic ductal adenocarcinoma reveal epigenetic deregulation of SLIT-ROBO, ITGA2 and MET signaling. Int. J. Cancer 135, 1110–1118 (2014)
    CAS PubMed Google Scholar
  31. Wang, Y. et al. Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. Nature Genet. 37, 750–755 (2005)
    CAS PubMed Google Scholar
  32. Doles, J. et al. Suppression of Rev3, the catalytic subunit of Polξ, sensitizes drug-resistant lung tumors to chemotherapy. Proc. Natl Acad. Sci. USA 107, 20786–20791 (2010)
    ADS CAS PubMed PubMed Central Google Scholar
  33. Chang, D. K., Grimmond, S. M., Evans, T. R. J. & Biankin, A. V. Mining the genomes of exceptional responders. Nature Rev. Cancer 14, 291–292 (2014)
    CAS Google Scholar
  34. Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009)
    CAS PubMed Google Scholar
  35. Deng, N. et al. A comprehensive survey of genomic alterations in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut 61, 673–684 (2012)
    CAS PubMed Google Scholar
  36. Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011)
  37. Cancer Genome Atlas Research Network. Comprehensive genomic characterization of squamous cell lung cancers. Nature 489, 519–525 (2012)
  38. Peddi, P. F. et al. Multi-institutional experience with FOLFIRINOX in pancreatic adenocarcinoma. JOP 13, 497–501 (2012)
    PubMed Google Scholar
  39. Villarroel, M. C. et al. Personalizing cancer treatment in the age of global genomic analyses: PALB2 gene mutations and the response to DNA damaging agents in pancreatic cancer. Mol. Cancer Ther. 10, 3–8 (2011)
    CAS PubMed Google Scholar
  40. Showalter, S. L. et al. Identifying pancreatic cancer patients for targeted treatment: the challenges and limitations of the current selection process and vision for the future. Expert Opin. Drug Deliv. 7, 273–284 (2010)
    CAS PubMed Google Scholar
  41. Golan, T. et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br. J. Cancer 111, 1132–1138 (2014)
    CAS PubMed PubMed Central Google Scholar
  42. Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009)
    CAS PubMed PubMed Central Google Scholar
  43. Sun, W. et al. Integrated study of copy number states and genotype calls using high-density SNP arrays. Nucleic Acids Res. 37, 5365–5377 (2009)
    CAS PubMed PubMed Central Google Scholar
  44. Krzywinski, M. et al. Circos: an information aesthetic for comparative genomics. Genome Res. 19, 1639–1645 (2009)
    CAS PubMed PubMed Central Google Scholar
  45. Nik-Zainal, S. et al. Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer. Nature Genet. 46, 487–491 (2014)
    CAS PubMed Google Scholar
  46. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010)
    CAS PubMed PubMed Central Google Scholar
  47. Ye, K., Schulz, M. H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009)
    CAS PubMed PubMed Central Google Scholar
  48. Thorvaldsdóttir, H., Robinson, J. T. & Mesirov, J. P. Integrative genomics viewer (IGV): high-performance genomics data visualization and exploration. Brief. Bioinform. 14, 178–192 (2013)
    PubMed Google Scholar
  49. Nik-Zainal, S. et al. Mutational processes molding the genomes of 21 breast cancers. Cell 149, 979–993 (2012)
    CAS PubMed PubMed Central Google Scholar
  50. Rubio-Viqueira, B. et al. An in vivo platform for translational drug development in pancreatic cancer. Clin. Cancer Res. 12, 4652–4661 (2006)
    CAS PubMed Google Scholar
  51. Rottenberg, S. et al. Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer. Proc. Natl Acad. Sci. USA 104, 12117–12122 (2007)
    ADS CAS PubMed PubMed Central Google Scholar
  52. Niclou, S. P. et al. A novel eGFP-expressing immunodeficient mouse model to study tumor-host interactions. FASEB J. 22, 3120–3128 (2008)
    CAS PubMed PubMed Central Google Scholar
  53. Graeser, M. et al. A marker of homologous recombination predicts pathologic complete response to neoadjuvant chemotherapy in primary breast cancer. Clin. Cancer Res. 16, 6159–6168 (2010)
    CAS PubMed PubMed Central Google Scholar

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Acknowledgements

We would like to thank C. Axford, 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 D. Gwynne for support at the Queensland Centre for Medical Genomics. We also thank M. Hodgins, M. Debeljak and D. Trusty for technical assistance at Johns Hopkins University. N. Sperandio and D. Filippini for technical assistance at Verona University. We acknowledge the following funding support: National Health and Medical Research Council of Australia (NHMRC; 631701, 535903, 427601); Queensland Government (NIRAP); University of Queensland; Institute for Molecular Bioscience; Cancer Research UK (C596/A18076, C29717/A17263); Australian Government: Department of Innovation, Industry, Science and Research (DIISR); Australian Cancer Research Foundation (ACRF); Cancer Council NSW: (SRP06-01, SRP11-01. ICGC); Cancer Institute NSW: (10/ECF/2-26; 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; University of Glasgow; Cancer Research UK; Howat Foundation; R.T. Hall Trust; Petre Foundation; Philip Hemstritch Foundation; 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); Italian Ministry of Research (Cancer Genome Project FIRB RBAP10AHJB); Associazione Italiana Ricerca Cancro (12182); Fondazione Italiana Malattie Pancreas – Ministero Salute (CUP_J33G13000210001); Wilhelm Sander Stiftung 2009.039.2; National Institutes of Health grant P50 CA62924.

Author information

Author notes

  1. Andrew V. Biankin and Sean M. Grimmond: These authors jointly supervised this work.
  2. Robert L. Sutherland: Deceased.
  3. andrew.biankin@glasgow.ac.uk

Authors and Affiliations

  1. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia,
    Nicola Waddell, Ann-Marie Patch, Karin S. Kassahn, Peter Bailey, David Miller, Katia Nones, Kelly Quek, Michael C. J. Quinn, Alan J. Robertson, Muhammad Z. H. Fadlullah, Tim J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Senel Idrisoglu, Suzanne Manning, Craig Nourse, Ehsan Nourbakhsh, Shivangi Wani, Peter J. Wilson, Emma Markham, Nicole Cloonan, Matthew J. Anderson, J. Lynn Fink, Oliver Holmes, Stephen H. Kazakoff, Conrad Leonard, Felicity Newell, Barsha Poudel, Sarah Song, Darrin Taylor, Nick Waddell, Scott Wood, Qinying Xu, John V. Pearson & Sean M. Grimmond
  2. QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia,
    Nicola Waddell, Nicole Cloonan & John V. Pearson
  3. Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia,
    Marina Pajic, David K. Chang, Amber L. Johns, Jianmin Wu, Mark Pinese, Mark J. Cowley, Hong C. Lee, Marc D. Jones, Adnan M. Nagrial, Jeremy Humphris, Lorraine A. Chantrill, Venessa Chin, Angela M. Steinmann, Amanda Mawson, Emily S. Humphrey, Emily K. Colvin, Angela Chou, Christopher J. Scarlett, Andreia V. Pinho, Marc Giry-Laterriere, Ilse Rooman, James G. Kench, Jessica A. Pettitt, Christopher Toon, Anthony J. Gill & Andrew V. Biankin
  4. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, 2010, New South Wales, Australia
    Marina Pajic
  5. Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia,
    David K. Chang, Neil D. Merrett & Andrew V. Biankin
  6. South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, 2170, New South Wales, Australia
    David K. Chang & Andrew V. Biankin
  7. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK,
    David K. Chang, Peter Bailey, Craig Nourse, Marc D. Jones, Nigel B. Jamieson, Janet S. Graham, Elizabeth A. Musgrove, Andrew V. Biankin & Sean M. Grimmond
  8. Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, 2010, New South Wales, Australia
    Angela Chou
  9. School of Environmental & Life Sciences, University of Newcastle, Ourimbah, 2258, New South Wales, Australia
    Christopher J. Scarlett
  10. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia,
    Jaswinder S. Samra
  11. University of Sydney, Sydney, 2006, New South Wales, Australia
    Jaswinder S. Samra, James G. Kench & Anthony J. Gill
  12. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, 2050, New South Wales, Australia
    James G. Kench
  13. School of Medicine, University of Western Sydney, Penrith, 2175, New South Wales, Australia
    Neil D. Merrett
  14. Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia,
    Krishna Epari
  15. Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia,
    Nam Q. Nguyen
  16. Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia,
    Andrew Barbour
  17. School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia,
    Nikolajs Zeps
  18. St John of God Pathology, 12 Salvado Rd, Subiaco, 6008, Western Australia, Australia
    Nikolajs Zeps
  19. Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, 6008, Western Australia, Australia
    Nikolajs Zeps
  20. Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK,
    Nigel B. Jamieson
  21. West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK,
    Nigel B. Jamieson
  22. Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK,
    Janet S. Graham
  23. Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg,
    Simone P. Niclou
  24. Department of Biomedicine, Norlux Neuro-Oncology, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway,
    Rolf Bjerkvig
  25. Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany,
    Robert Grützmann, Daniela Aust & Christian Pilarsky
  26. Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA
    Ralph H. Hruban, Richard A. Morgan & James R. Eshleman
  27. Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
    Anirban Maitra
  28. The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, New York, USA
    Christine A. Iacobuzio-Donahue
  29. Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA
    Christopher L. Wolfgang
  30. ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy,
    Rita T. Lawlor, Vincenzo Corbo & Aldo Scarpa
  31. Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy,
    Rita T. Lawlor, Giuseppe Zamboni & Aldo Scarpa
  32. Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy,
    Claudio Bassi & Massimo Falconi
  33. Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy,
    Massimo Falconi & Giuseppe Zamboni
  34. Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy,
    Giampaolo Tortora
  35. Division of Hematology and Oncology, University of California, San Francisco, 94122, California, USA
    Margaret A. Tempero
  36. The Kinghorn Cancer Centre, 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 H. 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, Angela Steinmann, Hong Ching Lee, Rachel Wong, Andreia V. Pinho, Marc Giry-Laterriere, Roger J. Daly, Elizabeth A. Musgrove, Robert L. Sutherland, Andrew V. Biankin, David K. Chang, Marc D. Jones, Andrew V. Biankin & David K. Chang
  37. Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow, Scotland G61 1BD, UK.,
    Andrew V. Biankin, David K. Chang, Marc D. Jones, Andrew V. Biankin, Sean M. Grimmond, David K. Chang, Elizabeth A. Musgrove, Marc D. Jones, Craig Nourse, Nigel B. Jamieson, Janet S. Graham, Andrew V. Biankin, David K. Chang, Nigel B. Jamieson, Janet S. Graham & Karen Oien
  38. Queensland Centre 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, Christina Xu, Katia Nones, J. Lynn Fink, Angelika Christ, Tim Bruxner, Nicole Cloonan, Felicity Newell, John V. Pearson, Peter Bailey, Michael Quinn, Shivashankar Nagaraj, Stephen Kazakoff, Nick Waddell, Keerthana Krisnan, Kelly Quek, David Wood, Muhammad Z. H. Fadlullah, Sean M. Grimmond & Craig Nourse
  39. Royal North Shore Hospital, Westbourne Street, St Leonards, New South Wales 2065, Australia.,
    Jaswinder S. Samra, Anthony J. Gill, Nick Pavlakis, Alex Guminski & Christopher Toon
  40. Bankstown Hospital, Eldridge Road, Bankstown, New South Wales 2200, Australia.,
    Ray Asghari, Neil D. Merrett, Darren Pavey & Amitabha Das
  41. Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, Australia.,
    Peter H. Cosman, Kasim Ismail & Chelsie O’Connnor
  42. Westmead Hospital, Hawkesbury and Darcy Roads, Westmead, New South Wales 2145, Australia.,
    Vincent W. Lam Duncan McLeod, 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 Forest, 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, South Australia 5000, Australia.,
    Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan & Tamara Debrencini
  48. Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042, 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, 237 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
  53. Johns Hopkins Medical Institute, 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 Hodgin
  54. ARC-NET Center for Applied Research on Cancer, University of Verona, Via dell’Artigliere, 19 37129 Verona, Province of Verona, Italy.,
    Aldo Scarpa, Rita T. Lawlor, Stefania Beghelli, Vincenzo Corbo, Maria Scardoni & Claudio Bassi
  55. University of California, San Francisco, 500 Parnassus Avenue, San Francisco, California 94122, USA.,
    Margaret A. Tempero
  56. Greater Glasgow and Clyde National Health Service, 1053 Great Western Road, Glasgow G12 0YN, UK.,
    Andrew V. Biankin, David K. Chang, Andrew V. Biankin, David K. Chang, Nigel B. Jamieson, Janet S. Graham, Andrew V. Biankin, David K. Chang, Nigel B. Jamieson, Janet S. Graham, Karen Oien & Jane Hair

Authors

  1. Nicola Waddell
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  2. Marina Pajic
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  3. Ann-Marie Patch
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  4. David K. Chang
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  5. Karin S. Kassahn
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  6. Peter Bailey
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  7. Amber L. Johns
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  8. David Miller
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  9. Katia Nones
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  10. Kelly Quek
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  11. Michael C. J. Quinn
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  12. Alan J. Robertson
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  13. Muhammad Z. H. Fadlullah
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  14. Tim J. C. Bruxner
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  15. Angelika N. Christ
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  16. Ivon Harliwong
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  17. Senel Idrisoglu
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  18. Suzanne Manning
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  19. Craig Nourse
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  20. Ehsan Nourbakhsh
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  21. Shivangi Wani
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  22. Peter J. Wilson
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  23. Emma Markham
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  24. Nicole Cloonan
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  25. Matthew J. Anderson
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  26. J. Lynn Fink
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  27. Oliver Holmes
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  28. Stephen H. Kazakoff
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  29. Conrad Leonard
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  30. Felicity Newell
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  31. Barsha Poudel
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  32. Sarah Song
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  33. Darrin Taylor
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  34. Nick Waddell
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  35. Scott Wood
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  36. Qinying Xu
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  37. Jianmin Wu
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  38. Mark Pinese
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  39. Mark J. Cowley
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  40. Hong C. Lee
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  41. Marc D. Jones
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Australian Pancreatic Cancer Genome Initiative

Contributions

Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the Queensland Centre for Medical Genomics. Investigator contributions are as follows: A.V.B. and S.M.G. (concept and design); S.M.G., J.V.P. N.W., A.V.B. (project leaders); N.W., S.M.G., D.K.C., A.V.B. (writing team); J.V.P., S.M.G., N.W., A.L.J., P.B., S.S., K.S.K., Nk.W., P.J.W., A.M.P., F.N., B.P., E.M., O.H., J.L.F., C.L., D.T., S.W., Q.X., K.N., N.C., M.C.J.Q., M.J.A., M.Z.H.F., A.J.R., S.K., K.Q., M.Pi., H.C.L., M.J.C. and J.W. (bioinformatics); M.Pa., C.J.S., D.K.C., E.S.H., A.M.N., A.C., A.S., C.S., A.V.P., I.R., A.M.S., S.P.N., R. B. (preclinical testing); A.L.J., M.D.J., M.P., C.J.S., C.T., A.M.N., V.T.C., L.A.C., J.S.S., D.K.C., V.C., A.S., C.S., A.J.G., J.A.L., I.R., A.V.P., E.A.M. (sample processing and quality control); A.J.G., J.G.K., C.T., G.Z., A.S., D.A. R.H.H., A.M., C.A.I-D., A.S. (pathology assessment); A.L.J., L.A.C., A.J.G., A.C., R.S.M., C.B., M.F., G.T., J.S.S., J.G.K., C.T., K.E., N.Q.N., N.Z., H.W., N.B.J., J.S.G, R.G., C.P., R.G., C.L.W., R.A.M., R.T.L., M.F., G.Z., G.T., M.A.T., A.P.G.I., J.R.E., R.H.H., A.M., C.A.I-D., A.S. (sample collection and clinical annotation); D.M., T.J.C.B., A.N.C., I.H., S.I., S.M., C.N., E.N., S.W. (sequencing). All authors have read and approved the final manuscript.

Corresponding authors

Correspondence toSean M. Grimmond or Sean M. Grimmond.

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Competing interests

The authors declare no competing financial interests.

Additional information

(Participants are arranged by institution.)

Extended data figures and tables

Extended Data Figure 1 Summary of structural rearrangements.

a, Histogram showing the number of events verified in silico or by orthogonal sequencing methods (Methods). In total 7,228 of the 11,868 events identified (61%) were verified, the others remain untested. These included 5,666 events which contained multiple lines of evidence (qSV category 1: discordant pairs, soft clipping on both sides and split read evidence, Methods) thus were considered verified. Of these events 2,463 events were also verified by orthogonal sequencing methods (SOLiD long mate pair or PCR amplicon sequencing) or the event was associated with a copy number change which was determined using SNP arrays. The remaining 1,562 events were verified using orthogonal sequencing methods or the event was associated with a copy number change (qSV category 2 and 3, Methods). b, Histogram showing the number of structural rearrangements in each pancreatic cancer. 100 PDACs were sequenced using HiSeq paired-end whole-genome sequencing. Structural rearrangements were identified and classified into 8 categories (deletions, duplications, tandem duplications, foldback inversions, amplified inversions, inversions, intra-chromosomal and inter-chromosomal translocations, Methods). The number and type of event for each patient is shown. PDAC shows a high degree of heterogeneity in both the number and types of events per patient. The structural rearrangements were used to classify the tumours into four categories (stable, locally rearranged, scattered and unstable, Methods).

Extended Data Figure 2 Distribution of structural variant breakpoints within each patient.

The 100 patients are plotted along the x axis. The upper plot shows the number of structural rearrangements (y axis) in each tumour. The lower plot shows which chromosomes (y axis) harbour clusters of breakpoints. The distribution of breakpoints (events per Mb) within each chromosome for each sample was evaluated using two methods to identify clusters of rearrangements or chromosomes which contain a large number of events. Method 1: chromosomes with a significant cluster of events were determined by a goodness-of-fit test against the expected exponential distribution (with a significance threshold of <0.0001). Chromosomes which pass these criteria are coloured blue. Method 2: chromosomes were identified which contain significantly more events per Mb than other chromosomes for that patient. Chromosomes were deemed to harbour a high number of events if they had a mutation rate per Mb which exceeds 1.5 times the length of the interquartile range from the 75th percentile of the chromosome counts for each patient. Chromosomes which pass these criteria are coloured orange. Chromosomes which pass both tests they are coloured red. These criteria show that the unstable tumours which contain many events often have significant clusters of events. In contrast locally rearranged tumours are associated with both clusters of events and a high number of events within that chromosome when compared to other chromosomes.

Extended Data Figure 3 The stable subtype in pancreatic ductal adenocarcinoma.

The 20 stable tumours are shown using circos. The coloured outer ring represents the chromosomes, the next ring depicts copy number (red represents gain and green represents loss), the next is the B allele frequency. The inner lines represent chromosome structural rearrangements detected by whole genome paired sequencing and the legend indicates the type of rearrangement. Stable tumours contained less than 50 structural rearrangements in each tumour.

Extended Data Figure 4 The locally rearranged subtype in pancreatic ductal adenocarcinoma.

The 30 locally rearranged tumours are shown using circos. The coloured outer rings represent the chromosomes, the next ring depicts copy number (red represents gain and green represents loss), the next is the B allele frequency. The inner lines represent chromosome structural rearrangements detected by whole-genome paired sequencing and the legend indicates the type of rearrangement. In the locally rearranged subtype over 25% of the structural rearrangements are clustered on one of few chromosomes.

Extended Data Figure 5 Example of evidence for chromothripsis in a pancreatic ductal adenocarcinoma (ICGC_0109).

Upper plot is a density plot showing a concentration of break-points on chromosome 5. Next panel shows the structural rearrangements which are coloured as presented in the legend. The lower panels show copy number, logR ratio and B allele frequency derived from SNP arrays. This chromosome showed a complex localization of events similar to chromothripsis. Copy number profile and structural rearrangements suggest a shattering of chromosome 5 with a high concentration of structural rearrangements, switches in copy number state and retention of heterozygosity, which are characteristics of a chromothriptic event.

Extended Data Figure 6 Example of evidence for breakage-fusion-bridge (BFB) in a pancreatic ductal adenocarcinoma (ICGC_0042).

Upper plot is a density plot showing a concentration of break-points on chromosome 5. Next panel shows the structural rearrangements which are coloured as presented in the legend. The lower panels show copy number, logR ratio and B allele frequency derived from SNP arrays. This chromosome showed a complex localization of events similar to BFB. Copy number profile suggests loss of telomeric q arm and a high concentration of structural rearrangements suggesting a series of BFB cycles, with multiple inversions mapped to the amplified regions.

Extended Data Figure 7 The scattered subtype in pancreatic ductal adenocarcinoma.

The 36 tumours classified as scattered are shown using circos. The coloured outer rings represent the chromosomes, the next ring depicts copy number (red represents gain and green represents loss), the next shows the B allele frequency. The inner lines represent chromosome structural rearrangements detected by whole genome paired end sequencing. The legend indicates the type of rearrangement. The scattered tumours contained 50–200 structural rearrangements in each tumour.

Extended Data Figure 8 The unstable subtype in pancreatic ductal adenocarcinoma.

The 14 unstable tumours are shown using circos. The coloured outer rings are chromosomes, the next ring depicts copy number (red represents gain and green represents loss), the next is the B allele frequency. The inner lines represent chromosome structural rearrangements detected by whole genome paired sequencing and the legend indicates the type of rearrangement. The unstable tumours contained a large degree of genomic instability and harboured over 200 structural rearrangements in each tumour which were predominantly intra-chromosomal rearrangements evenly distributed through the genome.

Extended Data Figure 9 RAD51 foci formation in a primary culture of genomically unstable PDAC.

a, RAD51 and geminin fluorescence in untreated cells derived from an unstable pancreatic tumour with a somatic mutation in the RPA1 gene (ICGC_0016). Primary culture of ICGC_0016 consists of eGFP+ mouse stromal and eGFP− tumour cells. b, Upper panel: irradiated unstable pancreatic cancer cells (ICGC_0016), middle panel: HR-competent (TKCC-07) and lower panel: HR-deficient (Capan-1) pancreatic tumour cells. Cells were irradiated in vitro with 10Gy, and 6 h post-irradiation examined by immunofluorescence microscopy. eGFP negative tumour cells from ICGC_0016 readily form RAD51 foci following induction of DNA damage. TKCC-07 is a pancreas cancer cell line generated from a homologous recombination (HR) pathway competent patient-derived xenograft and served as a positive control for staining and RAD51 foci formation after DNA damage. Capan-1 cells which are HR-deficient do not form RAD51 foci. c, RAD51 score (percentage of geminin positive cells that have RAD51 foci) in examined pancreatic tumour cells.

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Waddell, N., Pajic, M., Patch, AM. et al. Whole genomes redefine the mutational landscape of pancreatic cancer.Nature 518, 495–501 (2015). https://doi.org/10.1038/nature14169

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