Tumor Somatic Mutations Also Existing as Germline Polymorphisms May Help to Identify Functional SNPs from Genome-Wide Association Studies

Authors

Ivan P Gorlov
Xiangjun Xia
Spiridon Tsavachidis
Olga Y Gorlova
Christopher I Amos

Publication Date

10-15-2020

Journal

Carcinogenesis

DOI

10.1093/carcin/bgaa077

PMID

32681635

PMCID

PMC7566444

PubMedCentral® Posted Date

7-18-2020

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Genetic Predisposition to Disease, Genome-Wide Association Study, Germ-Line Mutation, Humans, Neoplasms, Polymorphism, Single Nucleotide, Risk

Abstract

We hypothesized that a joint analysis of cancer risk-associated single-nucleotide polymorphism (SNP) and somatic mutations in tumor samples can predict functional and potentially causal SNPs from GWASs. We used mutations reported in the Catalog of Somatic Mutations in Cancer (COSMIC). Confirmed somatic mutations were subdivided into two groups: (1) mutations reported as SNPs, which we call mutational/SNPs and (2) somatic mutations that are not reported as SNPs, which we call mutational/noSNPs. It is generally accepted that the number of times a somatic mutation is reported in COSMIC correlates with its selective advantage to tumors, with more frequently reported mutations being more functional and providing a stronger selective advantage to the tumor cell. We found that mutations reported ≥10 times in COSMIC-frequent mutational/SNPs (fmSNPs) are likely to be functional. We identified 12 cancer risk-associated SNPs reported in the Catalog of published GWASs at least 10 times as confirmed somatic mutations and therefore deemed to be functional. Additionally, we have identified 42 SNPs that are tightly linked (R2 ≥ 0.8) to SNPs reported in the Catalog of published GWASs as cancer risk associated and that are also reported as fmSNPs. As a result, 54 candidate functional/potentially causal cancer risk associated SNPs were identified. We found that fmSNPs are more likely to be located in evolutionarily conserved regions compared with cancer risk associated SNPs that are not fmSNPs. We also found that fmSNPs also underwent positive selection, which can explain why they exist as population polymorphisms.

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