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Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse
Loss of expression of Fhit, a tumor suppressor and genome caretaker, occurs in preneoplastic lesions during development of many human cancers. Furthermore, Fhit‐deficient mouse models are exquisitely susceptible to carcinogen induction of cancers of the lung and forestomach. Due to absence of Fhit g...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832848/ https://www.ncbi.nlm.nih.gov/pubmed/26782170 http://dx.doi.org/10.1111/cas.12887 |
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author | Paisie, Carolyn A. Schrock, Morgan S. Karras, Jenna R. Zhang, Jie Miuma, Satoshi Ouda, Iman M. Waters, Catherine E. Saldivar, Joshua C. Druck, Teresa Huebner, Kay |
author_facet | Paisie, Carolyn A. Schrock, Morgan S. Karras, Jenna R. Zhang, Jie Miuma, Satoshi Ouda, Iman M. Waters, Catherine E. Saldivar, Joshua C. Druck, Teresa Huebner, Kay |
author_sort | Paisie, Carolyn A. |
collection | PubMed |
description | Loss of expression of Fhit, a tumor suppressor and genome caretaker, occurs in preneoplastic lesions during development of many human cancers. Furthermore, Fhit‐deficient mouse models are exquisitely susceptible to carcinogen induction of cancers of the lung and forestomach. Due to absence of Fhit genome caretaker function, cultured cells and tissues of the constitutive Fhit knockout strain develop chromosome aneuploidy and allele copy number gains and losses and we hypothesized that Fhit‐deficient cells would also develop point mutations. On analysis of whole exome sequences of Fhit‐deficient tissues and cultured cells, we found 300 to >1000 single‐base substitutions associated with Fhit loss in the 2% of the genome included in exomes, relative to the C57Bl6 reference genome. The mutation signature is characterized by increased C>T and T>C mutations, similar to the “age at diagnosis” signature identified in human cancers. The Fhit‐deficiency mutation signature also resembles a C>T and T>C mutation signature reported for human papillary kidney cancers and a similar signature recently reported for esophageal and bladder cancers, cancers that are frequently Fhit deficient. The increase in T>C mutations in −/− exomes may be due to dNTP imbalance, particularly in thymidine triphosphate, resulting from decreased expression of thymidine kinase 1 in Fhit‐deficient cells. Fhit‐deficient kidney cells that survived in vitro dimethylbenz(a)anthracene treatment additionally showed increased T>A mutations, a signature generated by treatment with this carcinogen, suggesting that these T>A transversions may be evidence of carcinogen‐induced preneoplastic changes. |
format | Online Article Text |
id | pubmed-4832848 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-48328482016-04-20 Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse Paisie, Carolyn A. Schrock, Morgan S. Karras, Jenna R. Zhang, Jie Miuma, Satoshi Ouda, Iman M. Waters, Catherine E. Saldivar, Joshua C. Druck, Teresa Huebner, Kay Cancer Sci Original Articles Loss of expression of Fhit, a tumor suppressor and genome caretaker, occurs in preneoplastic lesions during development of many human cancers. Furthermore, Fhit‐deficient mouse models are exquisitely susceptible to carcinogen induction of cancers of the lung and forestomach. Due to absence of Fhit genome caretaker function, cultured cells and tissues of the constitutive Fhit knockout strain develop chromosome aneuploidy and allele copy number gains and losses and we hypothesized that Fhit‐deficient cells would also develop point mutations. On analysis of whole exome sequences of Fhit‐deficient tissues and cultured cells, we found 300 to >1000 single‐base substitutions associated with Fhit loss in the 2% of the genome included in exomes, relative to the C57Bl6 reference genome. The mutation signature is characterized by increased C>T and T>C mutations, similar to the “age at diagnosis” signature identified in human cancers. The Fhit‐deficiency mutation signature also resembles a C>T and T>C mutation signature reported for human papillary kidney cancers and a similar signature recently reported for esophageal and bladder cancers, cancers that are frequently Fhit deficient. The increase in T>C mutations in −/− exomes may be due to dNTP imbalance, particularly in thymidine triphosphate, resulting from decreased expression of thymidine kinase 1 in Fhit‐deficient cells. Fhit‐deficient kidney cells that survived in vitro dimethylbenz(a)anthracene treatment additionally showed increased T>A mutations, a signature generated by treatment with this carcinogen, suggesting that these T>A transversions may be evidence of carcinogen‐induced preneoplastic changes. John Wiley and Sons Inc. 2016-02-23 2016-04 /pmc/articles/PMC4832848/ /pubmed/26782170 http://dx.doi.org/10.1111/cas.12887 Text en © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial (http://creativecommons.org/licenses/by-nc/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. |
spellingShingle | Original Articles Paisie, Carolyn A. Schrock, Morgan S. Karras, Jenna R. Zhang, Jie Miuma, Satoshi Ouda, Iman M. Waters, Catherine E. Saldivar, Joshua C. Druck, Teresa Huebner, Kay Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title | Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title_full | Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title_fullStr | Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title_full_unstemmed | Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title_short | Exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive Fhit knockout mouse |
title_sort | exome‐wide single‐base substitutions in tissues and derived cell lines of the constitutive fhit knockout mouse |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4832848/ https://www.ncbi.nlm.nih.gov/pubmed/26782170 http://dx.doi.org/10.1111/cas.12887 |
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