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

Daniel Temko; Ian P M Tomlinson; Simone Severini; Benjamin Schuster-Böckler; Trevor A Graham

doi:10.1038/s41467-018-04208-6

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

Daniel Temko, Ian P M Tomlinson, Simone Severini, Benjamin Schuster-Böckler, Trevor A Graham

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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 language	English
Pages (from-to)	1857
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04208-6
Publication status	Published - 10 May 2018

Keywords / Materials (for Non-textual outputs)

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

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10.1038/s41467-018-04208-6

s41467-018-04208- nature comms
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title = "The effects of mutational processes and selection on driver mutations across cancer types",

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.",

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author = "Daniel Temko and Tomlinson, {Ian P M} and Simone Severini and Benjamin Schuster-B{\"o}ckler and Graham, {Trevor A}",

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AU - Temko, Daniel

AU - Tomlinson, Ian P M

AU - Severini, Simone

AU - Schuster-Böckler, Benjamin

AU - Graham, Trevor A

PY - 2018/5/10

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N2 - 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.

AB - 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.

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KW - Datasets as Topic

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KW - Gene Expression Regulation, Neoplastic/genetics

KW - Genes, Tumor Suppressor

KW - Genome, Human/genetics

KW - Humans

KW - Male

KW - Mutagens/toxicity

KW - Mutation Rate

KW - Neoplasms/etiology

KW - Oncogenes/genetics

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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