A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns

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• dc.contributor.author Notta, Faiyaz
• dc.contributor.author Chan-Seng-Yue, Michelle
• dc.contributor.author Lemire, Mathieu
• dc.contributor.author Li, Yilong
• dc.contributor.author Wilson, Gavin W.
• dc.contributor.author Connor, Ashton A.
• dc.contributor.author Denroche, Rob E.
• dc.contributor.author Liang, Sheng-Ben
• dc.contributor.author Brown, Andrew M.K.
• dc.contributor.author Kim, Jaeseung C.
• dc.contributor.author Wang, Tao
• dc.contributor.author Simpson, Jared T.
• dc.contributor.author Beck, Timothy
• dc.contributor.author Borgida, Ayelet
• dc.contributor.author Buchner, Nicholas
• dc.contributor.author Chadwick, Dianne
• dc.contributor.author Hafezi-Bakhtiari, Sara
• dc.contributor.author Dick, John E.
• dc.contributor.author Heisler, Lawrence
• dc.contributor.author Hollingsworth, Michael A.
• dc.contributor.author Ibrahimov, Emin
• dc.contributor.author Jang, Gun Ho
• dc.contributor.author Johns, Jeremy
• dc.contributor.author Jorgensen, Lars G.T.
• dc.contributor.author Law, Calvin
• dc.contributor.author Ludkovski, Olga
• dc.contributor.author Lungu, Ilinca
• dc.contributor.author Ng, Karen
• dc.contributor.author Pasternack, Danielle
• dc.contributor.author Petersen, Gloria M.
• dc.contributor.author Shlush, Liran I.
• dc.contributor.author Timms, Lee
• dc.contributor.author Tsao, Ming-Sound
• dc.contributor.author Wilson, Julie M.
• dc.contributor.author Yung, Christina K.
• dc.contributor.author Zogopoulos, George
• dc.contributor.author Bartlett, John M.S.
• dc.contributor.author Alexandrov, Ludmil B.
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Cleary, Sean P.
• dc.contributor.author Roehrl, Michael H.
• dc.contributor.author McPherson, John D.
• dc.contributor.author Stein, Lincoln D.
• dc.contributor.author Hudson, Thomas J.
• dc.contributor.author Campbell, Peter J.
• dc.contributor.author Gallinger, Steven
• dc.date.accessioned 2018-11-30T09:43:21Z
• dc.date.available 2018-11-30T09:43:21Z
• dc.date.issued 2016
• dc.description.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.
• dc.description.sponsorship 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
• dc.format.mimetype application/pdf
• dc.identifier.citation Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016 Oct 20;538(7625):378-82. DOI: 10.1038/nature19823
• dc.identifier.doi http://dx.doi.org/10.1038/nature19823
• dc.identifier.issn 0028-0836
• dc.identifier.uri http://hdl.handle.net/10230/35914
• dc.language.iso eng
• dc.publisher Nature Publishing Group
• dc.relation.ispartof Nature. 2016 Oct 20;538(7625):378-82
• dc.rights © Nature Publishing Group. Notta F, Chan-Seng-Yue M, Lemire M, Li Y, Wilson GW, Connor AA et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature. 2016 Oct 20; 538(7625): 378-382. http://dx.doi.org/10.1038/nature19823
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.other Carcinogènesi
• dc.subject.other Genoma humà
• dc.subject.other Models biològics
• dc.subject.other Mutagènesi
• dc.subject.other Pàncrees -- Tumors
• dc.title A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion