The effects of mutational processes and selection on driver mutations across cancer types
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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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Pancreatic cancer has a higher prevalence of G12R compared to lung adenocarcinoma and colorectal cancer, consistent with MAPK being the dominant signaling pathway driving pancreatic cancer.
“Compared to other KRAS-driven diseases like lung adenocarcinoma and colorectal cancer, pancreatic cancer has a higher prevalence of G12R, consistent with MAPK being the dominant signaling pathway driving pancreatic cancer [36,37].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [37]
The Results section, “Differential selection within driver genes” (page unavailable), reports stronger selection for KRAS G12R than for some other KRAS mutations in pancreatic cancer, while G12C is more strongly selected than G12R in lung adenocarcinoma. It does not establish that G12R prevalence is higher in pancreatic cancer than in both lung adenocarcinoma and colorectal cancer, or identify MAPK as the dominant pathway driving pancreatic cancer. (LLM, conf=0.84)
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- Authors
- Temko, D., Tomlinson, I. P. M., Severini, S., Schuster-Böckler, B., & Graham, T. A.
- Affiliations
- Queen Mary University of London (GB)
- University of Birmingham (GB)
- Corresponding author
- Temko, Daniel
- Graham, Trevor A.
- Venue
- Nature Communications
- Published
- 2018-05-10
- Volume
- 9
- Issue
- 1
- Pages
- 1857-1857
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5945620
- OpenAlex
- W2952767051
- Cited by
- 115
- References
- 2
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 8 · 2023: 20 · 2022: 15 · 2021: 12 · 2020: 25 · 2019: 18 · 2018: 2
- FWCI
- 4.31
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-04-20)
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion, cc-by)
- Funders
- Ludwig Institute for Cancer Research
- Wellcome Trust (202778, 202778/Z/16/Z)
- Cancer Research UK (A16459, 16459, A19771, 19771)
- Engineering and Physical Sciences Research Council (EP/F500351/1)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- driver mutations, mutational processes, natural selection, cancer genomics, APOBEC mutagenesis, DNA mismatch repair, smoking, aging, environmental mutagens, selection coefficients, cancer types
- MeSH terms
- Data Analysis, Chromosomes, Human, DNA Mutational Analysis, Environmental Exposure, Female, Humans, Male, Mutagens, Neoplasms, Oncogenes, Selection, Genetic, Genome, Human, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, DNA Mismatch Repair, Mutation Rate, Datasets as Topic
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