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).
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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
- Andrew V. Biankin and Sean M. Grimmond: These authors jointly supervised this work.
- Robert L. Sutherland: Deceased.
- andrew.biankin@glasgow.ac.uk
Authors and Affiliations
- 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 - QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia,
Nicola Waddell, Nicole Cloonan & John V. Pearson - 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 - St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, 2010, New South Wales, Australia
Marina Pajic - Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia,
David K. Chang, Neil D. Merrett & Andrew V. Biankin - 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 - 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 - Department of Anatomical Pathology, St Vincent’s Hospital, Sydney, 2010, New South Wales, Australia
Angela Chou - School of Environmental & Life Sciences, University of Newcastle, Ourimbah, 2258, New South Wales, Australia
Christopher J. Scarlett - Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia,
Jaswinder S. Samra - University of Sydney, Sydney, 2006, New South Wales, Australia
Jaswinder S. Samra, James G. Kench & Anthony J. Gill - Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, 2050, New South Wales, Australia
James G. Kench - School of Medicine, University of Western Sydney, Penrith, 2175, New South Wales, Australia
Neil D. Merrett - Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia,
Krishna Epari - Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia,
Nam Q. Nguyen - Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia,
Andrew Barbour - School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands 6009, Australia,
Nikolajs Zeps - St John of God Pathology, 12 Salvado Rd, Subiaco, 6008, Western Australia, Australia
Nikolajs Zeps - Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, 6008, Western Australia, Australia
Nikolajs Zeps - 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 - West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK,
Nigel B. Jamieson - Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK,
Janet S. Graham - Norlux Neuro-Oncology Laboratory, CRP-Santé Luxembourg, 84 Val Fleuri, L-1526, Luxembourg,
Simone P. Niclou - Department of Biomedicine, Norlux Neuro-Oncology, University of Bergen, Jonas Lies vei 91, N-5019 Bergen, Norway,
Rolf Bjerkvig - Departments of Surgery and Pathology, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany,
Robert Grützmann, Daniela Aust & Christian Pilarsky - 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 - Departments of Pathology and Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, 77030, Texas, USA
Anirban Maitra - 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 - Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, 21231, Maryland, USA
Christopher L. Wolfgang - ARC-NET Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy,
Rita T. Lawlor, Vincenzo Corbo & Aldo Scarpa - Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy,
Rita T. Lawlor, Giuseppe Zamboni & Aldo Scarpa - Department of Surgery and Oncology, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy,
Claudio Bassi & Massimo Falconi - Departments of Surgery and Pathology, Ospedale Sacro Cuore Don Calabria Negrar, Verona 37024, Italy,
Massimo Falconi & Giuseppe Zamboni - Department of Oncology, University and Hospital Trust of Verona, Verona 37134, Italy,
Giampaolo Tortora - Division of Hematology and Oncology, University of California, San Francisco, 94122, California, USA
Margaret A. Tempero - 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 - 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 - 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 - 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 - Bankstown Hospital, Eldridge Road, Bankstown, New South Wales 2200, Australia.,
Ray Asghari, Neil D. Merrett, Darren Pavey & Amitabha Das - Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, Australia.,
Peter H. Cosman, Kasim Ismail & Chelsie O’Connnor - 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 - 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 - 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 - Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, 6009, Western Australia, Australia
Nigel A. Spry, Bastiaan DeBoer & Ming Chai - St John of God Healthcare, 12 Salvado Road, Subiaco, Western Australia 6008, Australia.,
Nikolajs Zeps, Maria Beilin & Kynan Feeney - Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.,
Nan Q. Nguyen, Andrew R. Ruszkiewicz, Chris Worthley, Chuan P. Tan & Tamara Debrencini - Flinders Medical Centre, Flinders Drive, Bedford Park, South Australia 5042, Australia.,
John Chen, Mark E. Brooke-Smith & Virginia Papangelis - Greenslopes Private Hospital, Newdegate Street, Greenslopes, Queensland 4120, Australia.,
Henry Tang & Andrew P. Barbour - Envoi Pathology, 1/49 Butterfield Street, Herston, Queensland 4006, Australia.,
Andrew D. Clouston & Patrick Martin - 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 - Austin Hospital, 145 Studley Road, Heidelberg, Victoria 3084, Australia.,
Christopher Christophi, Mehrdad Nikfarjam & Angela Mountain - 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 - 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 - University of California, San Francisco, 500 Parnassus Avenue, San Francisco, California 94122, USA.,
Margaret A. Tempero - 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
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Consortia
Australian Pancreatic Cancer Genome Initiative
Garvan Institute of Medical Research
- 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
Queensland Centre for Medical Genomics / Institute for Molecular Biosciences
- 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
Royal North Shore Hospital
- Jaswinder S. Samra
- , Anthony J. Gill
- , Nick Pavlakis
- , Alex Guminski
- & Christopher Toon
Bankstown Hospital
- Ray Asghari
- , Neil D. Merrett
- , Darren Pavey
- & Amitabha Das
Liverpool Hospital
- Peter H. Cosman
- , Kasim Ismail
- & Chelsie O’Connnor
Westmead Hospital
- Vincent W. Lam Duncan McLeod
- , Henry C. Pleass
- , Arthur Richardson
- & Virginia James
Royal Prince Alfred Hospital
- James G. Kench
- , Caroline L. Cooper
- , David Joseph
- , Charbel Sandroussi
- , Michael Crawford
- & James Gallagher
Fremantle Hospital
- Michael Texler
- , Cindy Forest
- , Andrew Laycock
- , Krishna P. Epari
- , Mo Ballal
- , David R. Fletcher
- & Sanjay Mukhedkar
Sir Charles Gairdner Hospital
- Nigel A. Spry
- , Bastiaan DeBoer
- & Ming Chai
St John of God Healthcare
- Nikolajs Zeps
- , Maria Beilin
- & Kynan Feeney
Royal Adelaide Hospital
- Nan Q. Nguyen
- , Andrew R. Ruszkiewicz
- , Chris Worthley
- , Chuan P. Tan
- & Tamara Debrencini
Flinders Medical Centre
- John Chen
- , Mark E. Brooke-Smith
- & Virginia Papangelis
Greenslopes Private Hospital
- Henry Tang
- & Andrew P. Barbour
Envoi Pathology
- Andrew D. Clouston
- & Patrick Martin
Princess Alexandria Hospital
- Thomas J. O’Rourke
- , Amy Chiang
- , Jonathan W. Fawcett
- , Kellee Slater
- , Shinn Yeung
- , Michael Hatzifotis
- & Peter Hodgkinson
Austin Hospital
- Christopher Christophi
- , Mehrdad Nikfarjam
- & Angela Mountain
- , Victorian Cancer Biobank
Johns Hopkins Medical Institutes
- James R. Eshleman
- , Ralph H. Hruban
- , Anirban Maitra
- , Christine A. Iacobuzio-Donahue
- , Richard D. Schulick
- , Christopher L. Wolfgang
- , Richard A Morgan
- & Mary Hodgin
ARC-Net Centre for Applied Research on Cancer
- Aldo Scarpa
- , Rita T. Lawlor
- , Stefania Beghelli
- , Vincenzo Corbo
- , Maria Scardoni
- & Claudio Bassi
University of California, San Francisco
- Margaret A. Tempero
University of Glasgow
- Andrew V. Biankin
- , Sean M. Grimmond
- , David K. Chang
- , Elizabeth A. Musgrove
- , Marc D. Jones
- , Craig Nourse
- , Nigel B. Jamieson
- & Janet S. Graham
Greater Glasgow & Clyde National Health Service
- Andrew V. Biankin
- , David K. Chang
- , Nigel B. Jamieson
- , Janet S. Graham
- , Karen Oien
- & Jane Hair
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
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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
- Received: 24 May 2014
- Accepted: 18 December 2014
- Published: 25 February 2015
- Issue Date: 26 February 2015
- DOI: https://doi.org/10.1038/nature14169