• An Erratum to this article was published on 16 November 2016


Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development1. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations2,3,4,5 (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage2,5,6,7,8,9, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage10. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection11, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory12. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

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We would like to thank N. Simard, S. Zhao and members of the SickKids-UHN Flow facility for technical support. Funding sources for this study include grants to the Pancreatic Cancer Sequencing Initiative program from the Ontario Institute for Cancer Research (OICR), through support from the Ontario Ministry of Research and Innovation, the Canada Foundation for Innovation; research award to F.N. from the OICR and the Canadian Institutes for Health Research (CIHR); Canadian Friends of the Hebrew University, the SMGS Family Foundation, NCI grant P50 CA102701 (Mayo Clinic SPORE in Pancreatic Cancer) and NCI grant R01 CA97075 (Pancreatic Cancer Genetic Epidemiology Consortium). F.N. is supported by a fellowship award from CIHR and is a recipient of a scholar’s research award from the Ontario Institute of Cancer Research (OICR), through support from the Ontario Ministry of Research and Innovation. G.Z. is a Clinician–Scientist of the Fonds de la Recherche en Sante du Quebec. P.J.C. is a Wellcome Trust Senior Clinical Fellow. T.J.H., L.D.S., J.D.M. and S.G. are recipients of Senior or Clinician–Scientist Awards from the Ontario Institute for Cancer Research.

Author information

Author notes

    • Michelle Chan-Seng-Yue
    • , Mathieu Lemire
    •  & Yilong Li

    These authors contributed equally to this work


  1. Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada

    • Faiyaz Notta
    • , Michelle Chan-Seng-Yue
    • , Mathieu Lemire
    • , Gavin W. Wilson
    • , Ashton A. Connor
    • , Robert E. Denroche
    • , Andrew M. K. Brown
    • , Jaeseung C. Kim
    • , Jared T. Simpson
    • , Timothy Beck
    • , Nicholas Buchner
    • , Sara Hafezi-Bakhtiari
    • , John E. Dick
    • , Lawrence Heisler
    • , Emin Ibrahimov
    • , Gun Ho Jang
    • , Jeremy Johns
    • , Lars G. T. Jorgensen
    • , Ilinca Lungu
    • , Karen Ng
    • , Danielle Pasternack
    • , Lee Timms
    • , Julie M. Wilson
    • , Christina K. Yung
    • , John M. S. Bartlett
    • , John D. McPherson
    • , Lincoln D. Stein
    • , Thomas J. Hudson
    •  & Steven Gallinger
  2. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK

    • Yilong Li
    •  & Peter J. Campbell
  3. UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada

    • Sheng-Ben Liang
    • , Dianne Chadwick
    • , Sara Hafezi-Bakhtiari
    •  & Michael H. Roehrl
  4. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada

    • Jaeseung C. Kim
    • , Tao Wang
    • , Ming-Sound Tsao
    •  & John D. McPherson
  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

    • Tao Wang
  6. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

    • John E. Dick
    • , Lincoln D. Stein
    •  & Thomas J. Hudson
  7. Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada

    • Jared T. Simpson
  8. Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA

    • Ayelet Borgida
    •  & Michael A. Hollingsworth
  9. Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada

    • John E. Dick
    • , Olga Ludkovski
    • , Liran I. Shlush
    • , Ming-Sound Tsao
    •  & Michael H. Roehrl
  10. Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada

    • Calvin Law
  11. Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA

    • Gloria M. Petersen
  12. Research Institute of the McGill University Health Centre, Montreal, Québec, Canada, H3H 2L9

    • George Zogopoulos
  13. Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545

    • Ludmil B. Alexandrov
  14. Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain

    • Francisco X. Real
  15. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada

    • Sean P. Cleary
    •  & Steven Gallinger
  16. Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada

    • Sean P. Cleary
    •  & Steven Gallinger
  17. Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK

    • Peter J. Campbell


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Data analysis and interpretation was performed by F.N., M.L., Y.L., M.C.-S.-Y., G.W.W., A.A.C., F.X.R., P.J.C., S.G. and T.J.H.; tumour enrichment by S.-B.L., I.L. and F.N.; pathological assessment by T.W., M.-S.T., J.M.S.B., M.H.R. and S.H.-B.; genomics by R.E.D., A.M.K.B., K.N., J.C.K., L.T., N.B., D.P., L.H., E.I., G.H.J., J.J., L.G.T.J., J.D.M., L.D.S., L.I.S., L.H., J.E.D., C.K.Y., T.B. and L.B.A.; FISH by O.L.; CELLULOID analysis by M.L. and single-cell analysis by G.W.W., J.T.S. and F.N. Sample acquisition, annotation and collection from institutes external to University Health Network. was performed by G.M.P., M.A.H., G.Z. and C.L. Sample acquisition, annotation and collection from the University Health Network was performed by J.M.W., A.B., S.G. and S.P.C. The study was designed by F.N., T.J.H. and S.G.; F.N. prepared and wrote the manuscript; the manuscript was edited by M.L., F.X.R., J.E.D., P.J.C., T.J.H. and S.G.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Faiyaz Notta or Thomas J. Hudson.

Reviewer Information Nature thanks S. Chanock, M. Rossi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Information

    This file contains Supplementary Results, Supplementary Methods, Supplementary References, Supplementary Figures 1-18, Supplementary Tables 1-2 and Celluloid and Chrom-AL solutions data.

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