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Bleomycin-induced genome structural variations in normal, non-tumor cells

Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of...

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Autores principales: Quispe-Tintaya, Wilber, Lee, Moonsook, Dong, Xiao, Weiser, Daniel A., Vijg, Jan, Maslov, Alexander Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224559/
https://www.ncbi.nlm.nih.gov/pubmed/30410071
http://dx.doi.org/10.1038/s41598-018-34580-8
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author Quispe-Tintaya, Wilber
Lee, Moonsook
Dong, Xiao
Weiser, Daniel A.
Vijg, Jan
Maslov, Alexander Y.
author_facet Quispe-Tintaya, Wilber
Lee, Moonsook
Dong, Xiao
Weiser, Daniel A.
Vijg, Jan
Maslov, Alexander Y.
author_sort Quispe-Tintaya, Wilber
collection PubMed
description Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of these mutations, which are essentially only detectable in clonal outgrowths, such as tumors. Previously we developed Structural Variant Search (SVS) – an NGS-based assay for the quantitative detection of somatic GSVs in normal cells. Using an improved version of SVS we now demonstrate that the same dose of the anti-cancer drug bleomycin induces about 5 times more somatic GSVs in quiescent primary human fibroblasts than in proliferating cells. GVS induction in non-dividing, normal cells was subsequently confirmed in vivo by demonstrating that a single dose of bleomycin leads to a significant increase of GSV frequency in mouse liver and heart, two postmitotic tissues. Our findings suggest that normal non-cycling differentiated cells may serve as a reservoir of iatrogenically induced mutations. These results provide more insight into the possible molecular mechanisms that underlie late-life morbidities in cancer survivors exposed to chemotherapy.
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spelling pubmed-62245592018-11-13 Bleomycin-induced genome structural variations in normal, non-tumor cells Quispe-Tintaya, Wilber Lee, Moonsook Dong, Xiao Weiser, Daniel A. Vijg, Jan Maslov, Alexander Y. Sci Rep Article Many anticancer drugs are genotoxic agents inducing DNA breaks in actively proliferating cancer cells. However, these same drugs also induce mutations, mostly genome structural variations (GSVs). The detection of GSVs in normal cells and tissues is a major challenge due to the very low abundance of these mutations, which are essentially only detectable in clonal outgrowths, such as tumors. Previously we developed Structural Variant Search (SVS) – an NGS-based assay for the quantitative detection of somatic GSVs in normal cells. Using an improved version of SVS we now demonstrate that the same dose of the anti-cancer drug bleomycin induces about 5 times more somatic GSVs in quiescent primary human fibroblasts than in proliferating cells. GVS induction in non-dividing, normal cells was subsequently confirmed in vivo by demonstrating that a single dose of bleomycin leads to a significant increase of GSV frequency in mouse liver and heart, two postmitotic tissues. Our findings suggest that normal non-cycling differentiated cells may serve as a reservoir of iatrogenically induced mutations. These results provide more insight into the possible molecular mechanisms that underlie late-life morbidities in cancer survivors exposed to chemotherapy. Nature Publishing Group UK 2018-11-08 /pmc/articles/PMC6224559/ /pubmed/30410071 http://dx.doi.org/10.1038/s41598-018-34580-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Quispe-Tintaya, Wilber
Lee, Moonsook
Dong, Xiao
Weiser, Daniel A.
Vijg, Jan
Maslov, Alexander Y.
Bleomycin-induced genome structural variations in normal, non-tumor cells
title Bleomycin-induced genome structural variations in normal, non-tumor cells
title_full Bleomycin-induced genome structural variations in normal, non-tumor cells
title_fullStr Bleomycin-induced genome structural variations in normal, non-tumor cells
title_full_unstemmed Bleomycin-induced genome structural variations in normal, non-tumor cells
title_short Bleomycin-induced genome structural variations in normal, non-tumor cells
title_sort bleomycin-induced genome structural variations in normal, non-tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224559/
https://www.ncbi.nlm.nih.gov/pubmed/30410071
http://dx.doi.org/10.1038/s41598-018-34580-8
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