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.
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Data availability
HCT-116 sequence data used during the study have been deposited at the National Center for Biotechnology Information Sequence Read Archive under accession code PRJNA595067.
Code availability
R code to reproduce the figures is available at https://github.com/ucbtsl1/lopez_etal_2019_wgd-cancer.
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Acknowledgements
S.L. receives funding from Rosetrees. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of the Francis Crick Institute. C.S. is Royal Society Napier Research Professor. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (CRUK; FC001169 and FC001202), the UK Medical Research Council (FC001169 and FC001202) and the Wellcome Trust (FC001169 and FC001202). This work was supported by the CRUK City of London Centre Award (C7893/A26233). C.S. is funded by CRUK (TRACERx, PEACE and the CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, the Rosetrees Trust, the NovoNordisk Foundation (ID16584) and the Breast Cancer Research Foundation. This research is supported by a Stand Up To Cancer (SU2C)–LUNGevity Foundation–American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (grant number SU2C-AACR-DT23-17). SU2C is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research—the scientific partner of SU2C. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and Royal Society (grant number 211179/Z/18/Z), and also receives funding from the CRUK Lung Cancer Centre of Excellence, Rosetrees and the NIHR BRC at the University College London Hospitals. The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP7/2007-2013) Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet 607722), an ERC Advanced Grant (PROTEUS) from the ERC under the European Union’s Horizon 2020 research and innovation program (grant agreement 835297) and Chromavision from the European Union’s Horizon 2020 research and innovation program (grant agreement 665233). The results published here are in part based on data generated by the TCGA pilot project established by the NCI and the National Human Genome Research Institute. The data were retrieved through database of Genotypes and Phenotypes (dbGaP) authorization (accession number phs000178.v9.p8). Information about TCGA and the investigators and institutions that constitute the TCGA research network can be found at http://cancergenome.nih.gov/. We also thank C. McFarland for kindly sharing code for simulating deleterious alterations in cancer evolution.
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N.M. and C.S. conceptualized and supervised the study. S.L. and N.M. prepared the manuscript. S.L., C.S. and N.M. edited and reviewed the manuscript. S.H. and S.L. performed the simulations. S.L. and E.L.L. performed the formal analysis. S.L. visualized and presented the data. S.L., E.L.L., A.H., M.D., T.P.M., T.B.K.W., N.J.B., G.A.W. and N.M. curated the data and interpreted the results. S.M.D., A.R., K.H., P.V.L., M.J.-H., C.S. and N.M. provided resources.
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C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana and Boehringer-Ingelheim. C.S. has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi and the Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience and GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. N.M. has received consultancy fees from Achilles Therapeutics.
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López, S., Lim, E.L., Horswell, S. et al. Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution. Nat Genet 52, 283–293 (2020). https://doi.org/10.1038/s41588-020-0584-7
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DOI: https://doi.org/10.1038/s41588-020-0584-7
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