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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.

Original publication

DOI

10.1038/s41467-018-04208-6

Type

Journal article

Journal

Nat Commun

Publication Date

10/05/2018

Volume

9

Keywords

Chromosomes, Human, DNA Mismatch Repair, DNA Mutational Analysis, Data Analysis, Datasets as Topic, Environmental Exposure, Female, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Genome, Human, Humans, Male, Mutagens, Mutation Rate, Neoplasms, Oncogenes, Selection, Genetic