A weighted exact test for mutually exclusive mutations in cancer
Open accessAbstract
Motivation: The somatic mutations in the pathways that drive cancer development tend to be mutually exclusive across tumors, providing a signal for distinguishing driver mutations from a larger number of random passenger mutations. This mutual exclusivity signal can be confounded by high and highly variable mutation rates across a cohort of samples. Current statistical tests for exclusivity that incorporate both per-gene and per-sample mutational frequencies are computationally expensive and have limited precision. Results: We formulate a weighted exact test for assessing the significance of mutual exclusivity in an arbitrary number of mutational events. Our test conditions on the number of samples with a mutation as well as per-event, per-sample mutation probabilities. We provide a recursive formula to compute P-values for the weighted test exactly as well as a highly accurate and efficient saddlepoint approximation of the test. We use our test to approximate a commonly used permutation test for exclusivity that conditions on per-event, per-sample mutation frequencies. However, our test is more efficient and it recovers more significant results than the permutation test. We use our Weighted Exclusivity Test (WExT) software to analyze hundreds of colorectal and endometrial samples from The Cancer Genome Atlas, which are two cancer types that often have extremely high mutation rates. On both cancer types, the weighted test identifies sets of mutually exclusive mutations in cancer genes with fewer false positives than earlier approaches. Availability and Implementation: See http://compbio.cs.brown.edu/projects/wext for software. Contact: braphael@cs.brown.edu Supplementary information: Supplementary data are available at Bioinformatics online.
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The row-column exclusivity test conditions on both the frequency of mutation of the gene and the mutational burden of the samples.
“Thus, the test conditions on both the frequency of mutation of the gene and the mutational burden of the samples.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [37]
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- Authors
- Leiserson, M. D., Reyna, M. A., & Raphael, B. J.
- Affiliations
- Brown University (US)
- Corresponding author
- Raphael, Benjamin J
- Venue
- Bioinformatics
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-08-29
- Volume
- 32
- Issue
- 17
- Pages
- i736-i745
- ISSN
- 1367-4803 (ISSN-L)
- 1367-4811
- PMC
- PMC5013919
- OpenAlex
- W2592761229
- Cited by
- 56
- References
- 38
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 10 · 2020: 9 · 2019: 5 · 2018: 7 · 2017: 10
- FWCI
- 3.06
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Bioinformatics (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- National Institutes of Health
- NIH (R01HG005690, R01HG007069, R01CA180776)
- NSF (GRFP DGE 0228243)
- Burroughs Wellcome Fund
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Phylogenetic Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- mutually exclusive mutations, driver mutations, passenger mutations, somatic mutations, saddlepoint approximation, permutation tests, mutation rate, colorectal cancer, endometrial cancer, cancer genomics
- MeSH terms
- Algorithms, Humans, Mutation, Neoplasms, Probability, Software
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