Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk.

Publisher: Wiley-Liss Country of Publication: United States NLM ID: 8800109 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2280 (Electronic) Linking ISSN: 08936692 NLM ISO Abbreviation: Environ Mol Mutagen Subsets: MEDLINE

Publication: New York Ny : Wiley-Liss
Original Publication: New York, NY : Liss, c1987-

Mutation*/drug effects; Carcinogenesis/*genetics ; Neoplasms/*genetics; Animals ; Biomarkers, Tumor/genetics ; Carcinogenesis/chemically induced ; Carcinogens/toxicity ; High-Throughput Nucleotide Sequencing/methods ; Humans ; Neoplasms/chemically induced ; Risk Assessment/methods

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.
(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.)

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International U.S. Food and Drug Administration

Keywords: biomarker; cancer risk assessment; carcinogenesis; cell communication; cell signaling; mutation

0 (Biomarkers, Tumor)
0 (Carcinogens)

Date Created: 20190831 Date Completed: 20200717 Latest Revision: 20200717

20240829

PMC6973253

10.1002/em.22326

31469467