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Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution

Saioa López, Emilia Lim, Ariana Huebner, Michelle Dietzen, Thanos Mourikis, Thomas B.K. Watkins, Andrew Rowan, Sally M. Dewhurst, Nicolai J. Birkbak, Gareth A. Wilson, Mariam Jamal-Hanjani, Charles Swanton, on behalf of TRACERx Consortium, Nicholas McGranahan
doi: https://doi.org/10.1101/513457
Saioa López
1Cancer Genome Evolution Research Group, University College London Cancer Institute. London, UK
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
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Emilia Lim
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Ariana Huebner
1Cancer Genome Evolution Research Group, University College London Cancer Institute. London, UK
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Michelle Dietzen
1Cancer Genome Evolution Research Group, University College London Cancer Institute. London, UK
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Thanos Mourikis
1Cancer Genome Evolution Research Group, University College London Cancer Institute. London, UK
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
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Thomas B.K. Watkins
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Andrew Rowan
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Sally M. Dewhurst
4Laboratory for Cell Biology and Genetics. The Rockefeller University. New York, US
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Nicolai J. Birkbak
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
5Department of Molecular Medicine, Aarhus University, Aarhus, Denmark
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Gareth A. Wilson
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Mariam Jamal-Hanjani
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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Charles Swanton
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
3Cancer Evolution and Genome Instability Laboratory, the Francis Crick Institute and University College London Cancer Institute. London, UK
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  • For correspondence: charles.swanton@crick.ac.uk nicholas.mcgranahan.10@ucl.ac.uk
Nicholas McGranahan
1Cancer Genome Evolution Research Group, University College London Cancer Institute. London, UK
2Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute. London, UK
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  • For correspondence: charles.swanton@crick.ac.uk nicholas.mcgranahan.10@ucl.ac.uk
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Abstract

Whole genome doubling (WGD) is a prevalent macro-evolutionary event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and clinical prognostic relevance, the evolutionary selection pressures for WGD have not been investigated. Here, we explored whether WGD may act to mitigate the irreversible, inexorable ratchet-like, accumulation of deleterious mutations in essential genes. Utilizing 1050 tumor regions from 816 non-small cell lung cancers (NSCLC), we temporally dissect mutations to determine their temporal acquisition in relation to WGD. We find evidence for strong negative selection against homozygous loss of essential cancer genes prior to WGD. However, mutations in essential genes occurring after duplication were not subject to significant negative selection, consistent with WGD providing a buffering effect, decreasing the likelihood of homozygous loss. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify signals of positive selection in lung, breast, colorectal cancer and other cancer types, enabling the elucidation of novel tumour suppressor genes and a deeper characterization of known cancer genes.

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Posted January 07, 2019.
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Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution
Saioa López, Emilia Lim, Ariana Huebner, Michelle Dietzen, Thanos Mourikis, Thomas B.K. Watkins, Andrew Rowan, Sally M. Dewhurst, Nicolai J. Birkbak, Gareth A. Wilson, Mariam Jamal-Hanjani, Charles Swanton, on behalf of TRACERx Consortium, Nicholas McGranahan
bioRxiv 513457; doi: https://doi.org/10.1101/513457
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Whole Genome Doubling mitigates Muller’s Ratchet in Cancer Evolution
Saioa López, Emilia Lim, Ariana Huebner, Michelle Dietzen, Thanos Mourikis, Thomas B.K. Watkins, Andrew Rowan, Sally M. Dewhurst, Nicolai J. Birkbak, Gareth A. Wilson, Mariam Jamal-Hanjani, Charles Swanton, on behalf of TRACERx Consortium, Nicholas McGranahan
bioRxiv 513457; doi: https://doi.org/10.1101/513457

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