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

• Published in: Nature communications Vol. 9; no. 1; pp. 1857 - 10
• Main Authors: Temko, Daniel, Tomlinson, Ian P. M., Severini, Simone, Schuster-Böckler, Benjamin, Graham, Trevor A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.05.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 45; 631/114/2785; 631/67/69; 692/4028/67/69; Cancer; Chromosomes, Human - genetics; Data Analysis; Datasets as Topic; Deoxyribonucleic acid; DNA; DNA Mismatch Repair - genetics; DNA Mutational Analysis; DNA repair; Environmental Exposure - adverse effects; Epidemiology; Female; Gene Expression Regulation, Neoplastic - genetics; Genes, Tumor Suppressor; Genome, Human - genetics; Health risks; Humanities and Social Sciences; Humans; Male; Mismatch repair; multidisciplinary; Mutagens; Mutagens - toxicity; Mutation; Mutation Rate; Neoplasms - etiology; Neoplasms - genetics; Oncogenes - genetics; Science; Science (multidisciplinary); Selection, Genetic - genetics; Smoking
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04208-6

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. A central question in cancer research is how specific driver mutations are acquired and maintained during cancer development. Here Temko et al. use public sequencing data to infer the effect of mutation and selection on a set of driver mutations and suggest that selection frequently dominates.