| Literature DB >> 27732578 |
Faiyaz Notta1, Michelle Chan-Seng-Yue1, Mathieu Lemire1, Yilong Li2, Gavin W Wilson1, Ashton A Connor1, Robert E Denroche1, Sheng-Ben Liang3, Andrew M K Brown1, Jaeseung C Kim1,4, Tao Wang4,5, Jared T Simpson1,6, Timothy Beck1, Ayelet Borgida7, Nicholas Buchner1, Dianne Chadwick3, Sara Hafezi-Bakhtiari1,3, John E Dick1,8,9, Lawrence Heisler1, Michael A Hollingsworth7, Emin Ibrahimov1, Gun Ho Jang1, Jeremy Johns1, Lars G T Jorgensen1, Calvin Law10, Olga Ludkovski9, Ilinca Lungu1, Karen Ng1, Danielle Pasternack1, Gloria M Petersen11, Liran I Shlush9, Lee Timms1, Ming-Sound Tsao4,9, Julie M Wilson1, Christina K Yung1, George Zogopoulos12, John M S Bartlett1, Ludmil B Alexandrov13, Francisco X Real14, Sean P Cleary15,16, Michael H Roehrl3,9, John D McPherson1,4, Lincoln D Stein1,8, Thomas J Hudson1,8, Peter J Campbell2,17, Steven Gallinger1,15,16.
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.Entities:
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Year: 2016 PMID： 27732578 PMCID： PMC5446075 DOI： 10.1038/nature19823
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962