Article | Published:

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes

Nature volume 491, pages 399405 (15 November 2012) | Download Citation

This article has been updated

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.

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Change history

  • 14 November 2012

    The spelling of author ‘Qinying Xu’ was corrected; minor formatting changes were made to the Acknowledgements and Affiliations.

Accessions

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

Author notes

    • Robert L. Sutherland

    Deceased.

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, NewSouth Wales 2170, Australia.

    • Andrew V. Biankin
    •  & David K. Chang
  4. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, 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, New South Wales 2258, Australia.

    • Christopher J. Scarlett
  9. Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.

    • Anthony J. Gill
    •  & Jaswinder S. Samra
  10. University of Sydney, Sydney, New South Wales 2006, Australia.

    • Anthony J. Gill
    •  & James G. Kench
  11. Life Technologies, Brisbane, Queensland 4000, Australia.

    • Gabriel Kolle
  12. Department of Anatomical Pathology, Sydpath, St Vincent’s Hospital, Sydney, New South Wales 2010, Australia.

    • R. Scott Mead
    •  & Angela Chou
  13. Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia.

    • Jaswinder S. Samra
  14. Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia.

    • James G. Kench
  15. School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, 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, Callfornia 90024, 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, Minnesota 55905, 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, Maryland 21231, 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, Maryland 21231, 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. Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, and Department of Oncology, Robinson Way, Cambridge CB2 0RE, 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, Minnesota 55455, 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, Queensland 4072, 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, 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.

    • Andrew V. Biankin
    • , Ray Asghari
    • , Neil D. Merrett
    • , David K. Chang
    • , Darren A. Pavey
    •  & Amitabha Das
  41. Liverpool Hospital, Elizabeth Street, Liverpool, New South Wales 2170, 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, Western Australia 6009, 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.

    • Nam 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, 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

Consortia

  1. Australian Pancreatic Cancer Genome Initiative

    The Kinghorn Cancer Centre, Garvan Institute of Medical Research

    Queensland Center for Medical Genomics, Institute for Molecular Bioscience

    Royal North Shore Hospital

    Bankstown Hospital

    Liverpool Hospital

    Westmead Hospital

    Royal Prince Alfred Hospital

    Fremantle Hospital

    Sir Charles Gairdner Hospital

    St John of God Healthcare

    Royal Adelaide Hospital

    Flinders Medical Centre

    Greenslopes Private Hospital

    Envoi Pathology

    Princess Alexandria Hospital

    Austin Hospital

    Johns Hopkins Medical Institutes

    ARC-NET Center for Applied Research on Cancer

    University of California, San Francisco

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Contributions

The research network comprising the Australian Pancreatic Cancer Genome Initiative, the Baylor College of Medicine Cancer Genome Project and the Ontario Institute for Cancer Research Pancreatic Cancer Genome Study (ABO collaboration) contributed collectively to this study as part of the International Cancer Genome Consortium. Biospecimens were collected at affiliated hospitals and processed at each biospecimen core resource centre. Data generation and analyses were performed by the genome sequencing centres, cancer genome characterization centres and genome data analysis centres. Investigator contributions are as follows: S.M.G., A.V.B., J.V.P., R.L.S., R.A.G., D.A.W., M.-C.G., J.D.M., L.D.S and T.J.H. (project leaders); A.V.B., S.M.G. and R.L.S. (writing team); A.L.J., J.V.P., P.J.W., J.L.F., C.L., M.A., O.H., J.G.R., D.T., C.X., S.Wo., F.N., S.So., G.K. and W.K. (bioinformatics/databases); D.K.M., I.H., S.I., C.N., S.M., A.Chr., T.Br., S.Wa., E.N., B.B.G., D.M.M., Y.Q.W., Y.H., L.R.L., H.D., R. E. D., R.S.M. and M.W. (sequencing); N.W., K.S.K., J.V.P., A.-M.P., K.N., N.C., M.G., P.J.W., M.J.C., M.P., J.W., N.K., F.Z., J.D., K.C., C.J.B., L.B.M., D.P., R.E.D., R.D.B., T.Be. and C.K.Y. (mutation, copy number and gene expression analysis); A.L.J., D.K.C., M.D.J., M.P., C.J.S., E.K.C., C.T., A.M.N., E.S.H., V.T.C., L.A.C., E.N., J.S.S., J.L.H., C.T., N.B. and M.Sc. (sample processing and quality control); A.J.G., J.G.K., R.H.H., C.A.I.-D., A.Cho., A.Mai., J.R.E., P.C. and A.S. (pathology assessment); J.W., M.J.C., M.P., C.K.Y. and mutation analysis team (network/pathway analysis and functional data integration); K.M.M., N.A.J., N.G.C., P.A.P.-M., D.J.A., D.A.L., L.F.A.W., A.G.R., D.A.T., R.J.D., I.R., A.V.P., E.A.M., R.L.S., R.H.H. and A.Maw. (functional screens); E.N., A.L.J., J.S.S., A.J.G., J.G.K., N.D.M., A.B., K.E., N.Q.N., N.Z., W.E.F., F.C.B., S.E.H., G.E.A., L.M., L.T., M.Sam., K.B., A.B., D.P., A.P., N.B., R.D.B., R.E.D., C.Y., S.Se., N.O., D.M., M-S.T., P.A.S., G.M.P., S.G., L.D.S., C.A.I.-D., R.D.S., C.L.W., R.A.M., R.T.L., S.B., V.C., M.Sca., C.B., M.A.T., G.T., A.S. and J.R.E. (sample collection and clinical annotation); D.K.C., M.P., C.J.S., E.S.H., J.A.L., R.J.D., A.V.P. and I.R. (preclinical models).

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Sean M. Grimmond.

Supplementary information

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  1. 1.

    Supplementary Methods

    This file contains detailed Supplementary Methods and protocols.

Excel files

  1. 1.

    Supplementary Data

    This file contains Supplementary Tables 1-15 and Supplementary Figures 1-6.

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DOI

https://doi.org/10.1038/nature11547

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