Identification of Lung Cancer Drivers by Comparison of the Observed and the Expected Numbers of Missense and Nonsense Mutations in Individual Human Genes

Authors

Olga Y Gorlova
Marek Kimmel
Spiridon Tsavachidis
Christopher I Amos
Ivan P Gorlov

Publication Date

1-1-2022

Journal

Oncotarget

DOI

10.18632/oncotarget.28231

PMID

35634240

PMCID

PMC9132259

PubMedCentral® Posted Date

5-25-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Codon, Nonsense, Humans, Lung Neoplasms, Mutation, Mutation, Missense, Nucleotides, Oncogenes, lung cancer, somatic mutations, driver genes, Catalog Of Somatic Mutations In Cancer (COSMIC)

Abstract

Largely, cancer development is driven by acquisition and positive selection of somatic mutations that increase proliferation and survival of tumor cells. As a result, genes related to cancer development tend to have an excess of somatic mutations in them. An excess of missense and/or nonsense mutations in a gene is an indicator of its cancer relevance. To identify genes with an excess of potentially functional missense or nonsense mutations one needs to compare the observed and expected numbers of mutations in the gene. We estimated the expected numbers of missense and nonsense mutations in individual human genes using (i) the number of potential sites for missense and nonsense mutations in individual transcripts and (ii) histology-specific nucleotide context-dependent mutation rates. To estimate mutation rates defined as the number of mutations per site per tumor we used silent mutations reported in the Catalog Of Somatic Mutations In Cancer (COSMIC). The estimates were nucleotide context dependent. We have identified 26 genes with an excess of missense and/or nonsense mutations for lung adenocarcinoma, 18 genes for small cell lung cancer, and 26 genes for squamous cell carcinoma of the lung. These genes include known genes and novel lung cancer gene candidates.

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