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Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution

Item Type:Article
Title:Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution
Creators Name:López, S. and Lim, E.L. and Horswell, S. and Haase, K. and Huebner, A. and Dietzen, M. and Mourikis, T.P. and Watkins, T.B.K. and Rowan, A. and Dewhurst, S.M. and Birkbak, N.J. and Wilson, G.A. and Van Loo, P. and Jamal-Hanjani, M. and Swanton, C. and McGranahan, N.
Abstract:Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.
Keywords:Adenocarcinoma of Lung, Cohort Studies, Computer Simulation, DNA Copy Number Variations, Gene Duplication, Human Genome, Longitudinal Studies, Loss of Heterozygosity, Lung Neoplasms, Molecular Evolution, Mutation, Non-Small-Cell Lung Carcinoma, Prospective Studies, Squamous Cell Carcinoma, Tumor Suppressor Proteins
Source:Nature Genetics
Publisher:Nature Publishing Group
Page Range:283-293
Date:March 2020
Additional Information:Roland Schwarz is a member of the TRACERx Consortium. Copyright © 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.
Official Publication:https://doi.org/10.1038/s41588-020-0584-7
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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