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“Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk

It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with...

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Autores principales: Trosko, James E., Carruba, Giuseppe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: SAGE Publications 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502948/
https://www.ncbi.nlm.nih.gov/pubmed/28717349
http://dx.doi.org/10.1177/1559325817716585
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author Trosko, James E.
Carruba, Giuseppe
author_facet Trosko, James E.
Carruba, Giuseppe
author_sort Trosko, James E.
collection PubMed
description It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with mutations found in cancers associated with these exposures. While support for both interpretations provides some validity, both interpretations ignore several concepts of the multistage, multimechanism process of carcinogenesis, namely, (1) mutations can be generated by both “errors of DNA repair” and “errors of DNA replication,” during the “initiation” process of carcinogenesis; (2) “initiated” stem cells must be clonally amplified by nonmutagenic, intrinsic or extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be modified during in utero development, thereby altering the risk to cancer later in life; and (4) epigenetic tumor promoters are characterized by species, individual genetic-, gender-, developmental state-specificities, and threshold levels to be active; sustained and long-term exposures; and exposures in the absence of antioxidant “antipromoters.” Because of the inevitability of some of the stem cells generating “initiating” mutations by either “errors of DNA repair” or “errors of DNA replication,” a tumor is formed depending on the promotion phase of carcinogenesis. While it is possible to reduce our frequencies of mutagenic “initiated” cells, one can never reduce it to zero. Because of the extended period of the promotion phase of carcinogenesis, strategies to reduce the appearance of cancers must involve the interruption of the promotion of these initiated cells.
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spelling pubmed-55029482017-07-17 “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk Trosko, James E. Carruba, Giuseppe Dose Response Commentary It has been proposed that many human cancers are generated by intrinsic mechanisms that produce “Bad Luck” mutations by the proliferation of organ-specific adult stem cells. There have been serious challenges to this interpretation, including multiple extrinsic factors thought to be correlated with mutations found in cancers associated with these exposures. While support for both interpretations provides some validity, both interpretations ignore several concepts of the multistage, multimechanism process of carcinogenesis, namely, (1) mutations can be generated by both “errors of DNA repair” and “errors of DNA replication,” during the “initiation” process of carcinogenesis; (2) “initiated” stem cells must be clonally amplified by nonmutagenic, intrinsic or extrinsic epigenetic mechanisms; (3) organ-specific stem cell numbers can be modified during in utero development, thereby altering the risk to cancer later in life; and (4) epigenetic tumor promoters are characterized by species, individual genetic-, gender-, developmental state-specificities, and threshold levels to be active; sustained and long-term exposures; and exposures in the absence of antioxidant “antipromoters.” Because of the inevitability of some of the stem cells generating “initiating” mutations by either “errors of DNA repair” or “errors of DNA replication,” a tumor is formed depending on the promotion phase of carcinogenesis. While it is possible to reduce our frequencies of mutagenic “initiated” cells, one can never reduce it to zero. Because of the extended period of the promotion phase of carcinogenesis, strategies to reduce the appearance of cancers must involve the interruption of the promotion of these initiated cells. SAGE Publications 2017-06-30 /pmc/articles/PMC5502948/ /pubmed/28717349 http://dx.doi.org/10.1177/1559325817716585 Text en © The Author(s) 2017 http://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).
spellingShingle Commentary
Trosko, James E.
Carruba, Giuseppe
“Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title_full “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title_fullStr “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title_full_unstemmed “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title_short “Bad Luck Mutations”: DNA Mutations Are not the Whole Answer to Understanding Cancer Risk
title_sort “bad luck mutations”: dna mutations are not the whole answer to understanding cancer risk
topic Commentary
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502948/
https://www.ncbi.nlm.nih.gov/pubmed/28717349
http://dx.doi.org/10.1177/1559325817716585
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