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Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer
Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Impact Journals LLC
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741850/ https://www.ncbi.nlm.nih.gov/pubmed/26485759 |
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author | Nicolas, Emmanuelle Arora, Sanjeevani Zhou, Yan Serebriiskii, Ilya G. Andrake, Mark D. Handorf, Elizabeth D. Bodian, Dale L. Vockley, Joseph G. Dunbrack, Roland L. Ross, Eric A. Egleston, Brian L. Hall, Michael J. Golemis, Erica A. Giri, Veda N. Daly, Mary B. |
author_facet | Nicolas, Emmanuelle Arora, Sanjeevani Zhou, Yan Serebriiskii, Ilya G. Andrake, Mark D. Handorf, Elizabeth D. Bodian, Dale L. Vockley, Joseph G. Dunbrack, Roland L. Ross, Eric A. Egleston, Brian L. Hall, Michael J. Golemis, Erica A. Giri, Veda N. Daly, Mary B. |
author_sort | Nicolas, Emmanuelle |
collection | PubMed |
description | Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation. |
format | Online Article Text |
id | pubmed-4741850 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Impact Journals LLC |
record_format | MEDLINE/PubMed |
spelling | pubmed-47418502016-03-23 Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer Nicolas, Emmanuelle Arora, Sanjeevani Zhou, Yan Serebriiskii, Ilya G. Andrake, Mark D. Handorf, Elizabeth D. Bodian, Dale L. Vockley, Joseph G. Dunbrack, Roland L. Ross, Eric A. Egleston, Brian L. Hall, Michael J. Golemis, Erica A. Giri, Veda N. Daly, Mary B. Oncotarget Research Paper Risk assessment for prostate cancer is challenging due to its genetic heterogeneity. In this study, our goal was to develop an operational framework to select and evaluate gene variants that may contribute to familial prostate cancer risk. Drawing on orthogonal sources, we developed a candidate list of genes relevant to prostate cancer, then analyzed germline exomes from 12 case-only prostate cancer patients from high-risk families to identify patterns of protein-damaging gene variants. We described an average of 5 potentially disruptive variants in each individual and annotated them in the context of public databases representing human variation. Novel damaging variants were found in several genes of relevance to prostate cancer. Almost all patients had variants associated with defects in DNA damage response. Many also had variants linked to androgen signaling. Treatment of primary T-lymphocytes from these prostate cancer patients versus controls with DNA damaging agents showed elevated levels of the DNA double strand break (DSB) marker γH2AX (p < 0.05), supporting the idea of an underlying defect in DNA repair. This work suggests the value of focusing on underlying defects in DNA damage in familial prostate cancer risk assessment and demonstrates an operational framework for exome sequencing in case-only prostate cancer genetic evaluation. Impact Journals LLC 2015-10-14 /pmc/articles/PMC4741850/ /pubmed/26485759 Text en Copyright: © 2015 Nicolas et al. http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Paper Nicolas, Emmanuelle Arora, Sanjeevani Zhou, Yan Serebriiskii, Ilya G. Andrake, Mark D. Handorf, Elizabeth D. Bodian, Dale L. Vockley, Joseph G. Dunbrack, Roland L. Ross, Eric A. Egleston, Brian L. Hall, Michael J. Golemis, Erica A. Giri, Veda N. Daly, Mary B. Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title | Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title_full | Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title_fullStr | Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title_full_unstemmed | Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title_short | Systematic evaluation of underlying defects in DNA repair as an approach to case-only assessment of familial prostate cancer |
title_sort | systematic evaluation of underlying defects in dna repair as an approach to case-only assessment of familial prostate cancer |
topic | Research Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4741850/ https://www.ncbi.nlm.nih.gov/pubmed/26485759 |
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