title: A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.
abstract: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. 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 alterations (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 lineage, 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 stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, 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 trajectory. 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.
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Faiyaz
authors.initials: F
authors.lastname: Notta
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Chan-Seng-Yue
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Yilong
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authors.lastname: Li
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Gavin W
authors.initials: GW
authors.lastname: Wilson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Ashton A
authors.initials: AA
authors.lastname: Connor
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Denroche
authors.affiliation: UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Sheng-Ben
authors.initials: SB
authors.lastname: Liang
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Andrew M K
authors.initials: AM
authors.lastname: Brown
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
authors.forename: Jaeseung C
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.|Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada.
authors.forename: Jared T
authors.initials: JT
authors.lastname: Simpson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Timothy
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authors.lastname: Beck
authors.affiliation: Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Ayelet
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authors.lastname: Borgida
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.initials: N
authors.lastname: Buchner
authors.affiliation: UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Dianne
authors.initials: D
authors.lastname: Chadwick
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Sara
authors.initials: S
authors.lastname: Hafezi-Bakhtiari
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors.forename: John E
authors.initials: JE
authors.lastname: Dick
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Lawrence
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authors.affiliation: Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hollingsworth
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Emin
authors.initials: E
authors.lastname: Ibrahimov
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Gun Ho
authors.initials: GH
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.lastname: Johns
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.initials: LG
authors.lastname: Jorgensen
authors.affiliation: Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada.
authors.forename: Calvin
authors.initials: C
authors.lastname: Law
authors.affiliation: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Ludkovski
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Ilinca
authors.initials: I
authors.lastname: Lungu
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.initials: K
authors.lastname: Ng
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.lastname: Pasternack
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.
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authors.affiliation: Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
authors.forename: Lee
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authors.lastname: Timms
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.|Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors.forename: Ming-Sound
authors.initials: MS
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.initials: JM
authors.lastname: Wilson
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
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authors.initials: JM
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authors.affiliation: Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545.
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authors.forename: Francisco X
authors.initials: FX
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authors.affiliation: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada.
authors.forename: Sean P
authors.initials: SP
authors.lastname: Cleary
authors.affiliation: UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada.|Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Roehrl
authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
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authors.initials: JD
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
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authors.initials: LD
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Thomas J
authors.initials: TJ
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authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.|Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK.
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authors.initials: PJ
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authors.affiliation: Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.|Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada.
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mesh_terms: D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics; D000072837:Chromothripsis; D056915:DNA Copy Number Variations / Q000235:genetics; D018450:Disease Progression; D019143:Evolution, Molecular; D005260:Female; D015321:Gene Rearrangement / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D008938:Mitosis / Q000235:genetics; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D011123:Polyploidy; D011230:Precancerous Conditions / Q000235:genetics