1. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns
- Author
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George Zogopoulos, Mathieu Lemire, Thomas J. Hudson, Michael A. Hollingsworth, Robert E. Denroche, Faiyaz Notta, Jeremy Johns, Michael H.A. Roehrl, Francisco X. Real, Ayelet Borgida, Dianne Chadwick, Ashton A. Connor, John E. Dick, Peter J. Campbell, John Douglas Mcpherson, Jared T. Simpson, Lee Timms, Olga Ludkovski, Calvin Law, Nicholas Buchner, Emin Ibrahimov, Sean P. Cleary, Christina K. Yung, J. Kim, Lincoln Stein, Gun Ho Jang, Karen Ng, Ludmil B. Alexandrov, Lars G.T. Jorgensen, Gavin W. Wilson, Steven Gallinger, Ilinca Lungu, John M. S. Bartlett, Lawrence E. Heisler, Gloria M. Petersen, Tao Wang, Sheng Ben Liang, Andrew M.K. Brown, Sara Hafezi-Bakhtiari, Timothy Beck, Julie M. Wilson, Danielle Pasternack, Liran I. Shlush, Michelle Chan-Seng-Yue, Ming-Sound Tsao, and Yang Li
- Subjects
Male ,0301 basic medicine ,Pàncrees -- Tumors ,Carcinogenesis ,Genoma humà ,Bioinformatics ,medicine.disease_cause ,0302 clinical medicine ,Models ,CDKN2A ,2.1 Biological and endogenous factors ,Carcinogènesi ,Neoplasm Metastasis ,Aetiology ,Cancer ,Gene Rearrangement ,Genome ,Multidisciplinary ,Chromothripsis ,Models biològics ,5.1 Pharmaceuticals ,030220 oncology & carcinogenesis ,Mutagènesi ,Disease Progression ,Female ,KRAS ,Development of treatments and therapeutic interventions ,Carcinoma in Situ ,Human ,Biotechnology ,Lineage (genetic) ,DNA Copy Number Variations ,Evolution ,General Science & Technology ,Mitosis ,Biology ,Models, Biological ,Evolution, Molecular ,Polyploidy ,Pancreatic Cancer ,03 medical and health sciences ,Rare Diseases ,Pancreatic cancer ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Genome, Human ,Carcinoma in situ ,Human Genome ,Molecular ,Gene rearrangement ,Biological ,medicine.disease ,Pancreatic Neoplasms ,Orphan Drug ,030104 developmental biology ,Genes ,Mutagenesis ,Mutation ,Neoplasm ,Digestive Diseases ,Precancerous Conditions ,Genes, Neoplasm - 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. 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
- Published
- 2016