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.

DOI: 10.1038/nature19823
05010020162017
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@article{Notta2016ARM, title={A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns.}, author={Faiyaz Notta and Michelle A Chan-Seng-Yue and Mathieu Lemire and Yilong Li and Gavin W. Wilson and Ashton A. Connor and Robert E Denroche and Sheng-ben Liang and Andrew M. K. Brown and Jaeseung C Kim and Tao Wang and Jared T. Simpson and Timothy A Beck and Ayelet Eppel Borgida and Nicholas B Buchner and Dianne Chadwick and Sara Hafezi-Bakhtiari and John E Dick and Lawrence E. Heisler and Michael Anthony Hollingsworth and E. A. Ibrahimov and Gun Ho Jang and Jeremy Johns and Lars G T Jorgensen and Calvin H. L. Law and Olga Ludkovski and Ilinca Mihaela Lungu and Karen M. Y. Ng and Danielle Pasternack and Gloria M Petersen and Liran I. Shlush and Lee Timms and Ming-Sound Tsao and Julie M Wilson and Christina K. Yung and George Zogopoulos and John M. S. Bartlett and Ludmil B Alexandrov and Francisco X Real and Sean P. Cleary and Michael H. A. Roehrl and John D. McPherson and Lincoln Stein and Thomas J. Hudson and Peter J. Campbell and Steven Gallinger}, journal={Nature}, year={2016}, volume={538 7625}, pages={378-382} }