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

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...

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Autores principales: Harris, Kelly L., Myers, Meagan B., McKim, Karen L., Elespuru, Rosalie K., Parsons, Barbara L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973253/
https://www.ncbi.nlm.nih.gov/pubmed/31469467
http://dx.doi.org/10.1002/em.22326
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author Harris, Kelly L.
Myers, Meagan B.
McKim, Karen L.
Elespuru, Rosalie K.
Parsons, Barbara L.
author_facet Harris, Kelly L.
Myers, Meagan B.
McKim, Karen L.
Elespuru, Rosalie K.
Parsons, Barbara L.
author_sort Harris, Kelly L.
collection PubMed
description 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.
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spelling pubmed-69732532020-01-27 Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk Harris, Kelly L. Myers, Meagan B. McKim, Karen L. Elespuru, Rosalie K. Parsons, Barbara L. Environ Mol Mutagen Reviews 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. John Wiley & Sons, Inc. 2019-10-06 2020-01 /pmc/articles/PMC6973253/ /pubmed/31469467 http://dx.doi.org/10.1002/em.22326 Text en 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. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Reviews
Harris, Kelly L.
Myers, Meagan B.
McKim, Karen L.
Elespuru, Rosalie K.
Parsons, Barbara L.
Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title_full Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title_fullStr Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title_full_unstemmed Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title_short Rationale and Roadmap for Developing Panels of Hotspot Cancer Driver Gene Mutations as Biomarkers of Cancer Risk
title_sort rationale and roadmap for developing panels of hotspot cancer driver gene mutations as biomarkers of cancer risk
topic Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6973253/
https://www.ncbi.nlm.nih.gov/pubmed/31469467
http://dx.doi.org/10.1002/em.22326
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