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The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers

Pathogenic germline variants in checkpoint kinase 2 (CHEK2), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from CHEK2 germline mutation carriers (16 h...

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Autores principales: Mandelker, Diana, Kumar, Rahul, Pei, Xin, Selenica, Pier, Setton, Jeremy, Arunachalam, Sasi, Ceyhan-Birsoy, Ozge, Brown, David N, Norton, Larry, Robson, Mark E, Wen, Hannah Y, Powell, Simon, Riaz, Nadeem, Weigelt, Britta, Reis-Filho, Jorge S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649818/
https://www.ncbi.nlm.nih.gov/pubmed/31360903
http://dx.doi.org/10.1093/jncics/pkz027
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author Mandelker, Diana
Kumar, Rahul
Pei, Xin
Selenica, Pier
Setton, Jeremy
Arunachalam, Sasi
Ceyhan-Birsoy, Ozge
Brown, David N
Norton, Larry
Robson, Mark E
Wen, Hannah Y
Powell, Simon
Riaz, Nadeem
Weigelt, Britta
Reis-Filho, Jorge S
author_facet Mandelker, Diana
Kumar, Rahul
Pei, Xin
Selenica, Pier
Setton, Jeremy
Arunachalam, Sasi
Ceyhan-Birsoy, Ozge
Brown, David N
Norton, Larry
Robson, Mark E
Wen, Hannah Y
Powell, Simon
Riaz, Nadeem
Weigelt, Britta
Reis-Filho, Jorge S
author_sort Mandelker, Diana
collection PubMed
description Pathogenic germline variants in checkpoint kinase 2 (CHEK2), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from CHEK2 germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). CHEK2-associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the CHEK2 wild-type allele. Conversely, CHEK2-associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. CHEK2-associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that CHEK2-associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of ATM-associated BCs. Specific CHEK2 germline variants may have a distinct impact on tumor biology.
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spelling pubmed-66498182019-07-29 The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers Mandelker, Diana Kumar, Rahul Pei, Xin Selenica, Pier Setton, Jeremy Arunachalam, Sasi Ceyhan-Birsoy, Ozge Brown, David N Norton, Larry Robson, Mark E Wen, Hannah Y Powell, Simon Riaz, Nadeem Weigelt, Britta Reis-Filho, Jorge S JNCI Cancer Spectr Brief Communication Pathogenic germline variants in checkpoint kinase 2 (CHEK2), which plays pivotal roles in DNA damage response and cell cycle regulation, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic and genomic characteristics of 33 BCs from CHEK2 germline mutation carriers (16 high-risk variants and 17 low-risk p.Ile157Thr variants). CHEK2-associated BCs from patients with high-risk germline variants were largely hormone receptor-positive (87%, 13/15), and 81% (13/16) exhibited loss of heterozygosity (LOH) of the CHEK2 wild-type allele. Conversely, CHEK2-associated BCs from patients with the low-risk p.Ile157Thr variant displayed less-frequent loss of heterozygosity (5/17, 29%) and higher levels of CHEK2 protein expression than those with high-risk germline variants. CHEK2-associated BCs lacked a dominant mutational signature 3, a genomics feature of homologous recombination DNA repair deficiency (HRD). Our findings indicate that CHEK2-associated BCs are generally hormone receptor-positive and lack HRD-related mutational signatures, recapitulating the features of ATM-associated BCs. Specific CHEK2 germline variants may have a distinct impact on tumor biology. Oxford University Press 2019-04-27 /pmc/articles/PMC6649818/ /pubmed/31360903 http://dx.doi.org/10.1093/jncics/pkz027 Text en © The Author(s) 2019. Published by Oxford University Press. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Brief Communication
Mandelker, Diana
Kumar, Rahul
Pei, Xin
Selenica, Pier
Setton, Jeremy
Arunachalam, Sasi
Ceyhan-Birsoy, Ozge
Brown, David N
Norton, Larry
Robson, Mark E
Wen, Hannah Y
Powell, Simon
Riaz, Nadeem
Weigelt, Britta
Reis-Filho, Jorge S
The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title_full The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title_fullStr The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title_full_unstemmed The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title_short The Landscape of Somatic Genetic Alterations in Breast Cancers from CHEK2 Germline Mutation Carriers
title_sort landscape of somatic genetic alterations in breast cancers from chek2 germline mutation carriers
topic Brief Communication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649818/
https://www.ncbi.nlm.nih.gov/pubmed/31360903
http://dx.doi.org/10.1093/jncics/pkz027
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