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Nat Commun. 2018 May 10;9(1):1857. doi: 10.1038/s41467-018-04208-6.

The effects of mutational processes and selection on driver mutations across cancer types.

Author information

1
Evolution and Cancer laboratory, Barts Cancer Institute, QMUL, Charterhouse Sq, London, EC1M 6BQ, UK. daniel.temko.13@ucl.ac.uk.
2
Department of Computer Science, University College London, London, WC1E 6BT, UK. daniel.temko.13@ucl.ac.uk.
3
Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, Gower Street, London, WC1E 6BT, UK. daniel.temko.13@ucl.ac.uk.
4
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, B15 2TT, UK.
5
Department of Computer Science, University College London, London, WC1E 6BT, UK.
6
Institute of Natural Sciences, Shanghai Jiao Tong University, Dong Chuan Road, Minhang District, Shanghai, 200240, UK.
7
Ludwig Institute for Cancer Research, University of Oxford, Old Road Campus Research Building, Roosevelt Dr, Oxford, OX3 7DQ, USA. benjamin.schuster-boeckler@ludwig.ox.ac.uk.
8
Evolution and Cancer laboratory, Barts Cancer Institute, QMUL, Charterhouse Sq, London, EC1M 6BQ, UK. t.graham@qmul.ac.uk.

Abstract

Epidemiological evidence has long associated environmental mutagens with increased cancer risk. However, links between specific mutation-causing processes and the acquisition of individual driver mutations have remained obscure. Here we have used public cancer sequencing data from 11,336 cancers of various types to infer the independent effects of mutation and selection on the set of driver mutations in a cancer type. First, we detect associations between a range of mutational processes, including those linked to smoking, ageing, APOBEC and DNA mismatch repair (MMR) and the presence of key driver mutations across cancer types. Second, we quantify differential selection between well-known alternative driver mutations, including differences in selection between distinct mutant residues in the same gene. These results show that while mutational processes have a large role in determining which driver mutations are present in a cancer, the role of selection frequently dominates.

PMID:
29748584
PMCID:
PMC5945620
DOI:
10.1038/s41467-018-04208-6
[Indexed for MEDLINE]
Free PMC Article

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