Abstract
Cancer driver mutations (CDMs) are necessary and causal for carcinogenesis and have advantages as reporters of carcinogenic risk. However, little progress has been made toward developing measurements of CDMs as biomarkers for use in cancer risk assessment. Impediments for using a CDM‐based metric to inform cancer risk include the complexity and stochastic nature of carcinogenesis, technical difficulty in quantifying low‐frequency CDMs, and lack of established relationships between cancer driver mutant fractions and tumor incidence. Through literature review and database analyses, this review identifies the most promising targets to investigate as biomarkers of cancer risk. Mutational hotspots were discerned within the 20 most mutated genes across the 10 deadliest cancers. Forty genes were identified that encompass 108 mutational hotspot codons overrepresented in the COSMIC database; 424 different mutations within these hotspot codons account for approximately 63,000 tumors and their prevalence across tumor types is described. The review summarizes literature on the prevalence of CDMs in normal tissues and suggests such mutations are direct and indirect substrates for chemical carcinogenesis, which occurs in a spatially stochastic manner. Evidence that hotspot CDMs (hCDMs) frequently occur as tumor subpopulations is presented, indicating COSMIC data may underestimate mutation prevalence. Analyses of online databases show that genes containing hCDMs are enriched in functions related to intercellular communication. In its totality, the review provides a roadmap for the development of tissue‐specific, CDM‐based biomarkers of carcinogenic potential, comprised of batteries of hCDMs and can be measured by error‐correct next‐generation sequencing. Environ. Mol. Mutagen. 61:152–175, 2020. Published 2019. This article is a U.S. Government work and is in the public domain in the USA. Environmental and Molecular Mutagenesis published by Wiley Periodicals, Inc. on behalf of Environmental Mutagen Society.
Highlights
Cancer driver mutations (CDMs) have potential as biomarkers for use in carcinogenicity testing and assessing potential cancer risks associated with exogenous exposures, whether therapeutic, occupational, or environmental
When the two groups were compared in terms of the numbers of genes involved in either autocrine, juxtacrine, paracrine, and endocrine signaling using Fisher’s exact test, significant enrichment of functions related to cell communication was observed in the genes identified as encompassing hotspot CDMs (hCDMs) compared to Tier 1 and Tier 2 genes with point
This review summarizes literature relevant to the concept of using measurements of hCDMs as an approach to develop composite, molecular, safety biomarkers, with a context of use related to the analysis of test articles in short-term rodent studies
Summary
Cancer driver mutations (CDMs) have potential as biomarkers for use in carcinogenicity testing and assessing potential cancer risks associated with exogenous exposures, whether therapeutic, occupational, or environmental. Analyses over the last 20 years have yielded a quantitative understanding of CDM levels across normal tissues and tumors, for hCDMs. The literature indicating CDMs are prevalent in normal human tissues and occur in remarkably high percentages of tumors as mutant subpopulations are presented here, along with a systematic analysis of the most highly mutated genes, based on COSMIC data.
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