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Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer

BACKGROUND: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions...

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Autores principales: Wen, Hongxiu, Kim, Yeong C, Snyder, Carrie, Xiao, Fengxia, Fleissner, Elizabeth A, Becirovic, Dina, Luo, Jiangtao, Downs, Bradley, Sherman, Simon, Cowan, Kenneth H, Lynch, Henry T, Wang, San Ming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083142/
https://www.ncbi.nlm.nih.gov/pubmed/24969172
http://dx.doi.org/10.1186/1471-2407-14-470
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author Wen, Hongxiu
Kim, Yeong C
Snyder, Carrie
Xiao, Fengxia
Fleissner, Elizabeth A
Becirovic, Dina
Luo, Jiangtao
Downs, Bradley
Sherman, Simon
Cowan, Kenneth H
Lynch, Henry T
Wang, San Ming
author_facet Wen, Hongxiu
Kim, Yeong C
Snyder, Carrie
Xiao, Fengxia
Fleissner, Elizabeth A
Becirovic, Dina
Luo, Jiangtao
Downs, Bradley
Sherman, Simon
Cowan, Kenneth H
Lynch, Henry T
Wang, San Ming
author_sort Wen, Hongxiu
collection PubMed
description BACKGROUND: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family. METHODS: In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer. RESULTS: We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation. CONCLUSIONS: Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions.
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spelling pubmed-40831422014-07-08 Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer Wen, Hongxiu Kim, Yeong C Snyder, Carrie Xiao, Fengxia Fleissner, Elizabeth A Becirovic, Dina Luo, Jiangtao Downs, Bradley Sherman, Simon Cowan, Kenneth H Lynch, Henry T Wang, San Ming BMC Cancer Research Article BACKGROUND: Genetic predisposition is the primary risk factor for familial breast cancer. For the majority of familial breast cancer, however, the genetic predispositions remain unknown. All newly identified predispositions occur rarely in disease population, and the unknown genetic predispositions are estimated to reach up to total thousands. Family unit is the basic structure of genetics. Because it is an autosomal dominant disease, individuals with a history of familial breast cancer must carry the same genetic predisposition across generations. Therefore, focusing on the cases in lineages of familial breast cancer, rather than pooled cases in disease population, is expected to provide high probability to identify the genetic predisposition for each family. METHODS: In this study, we tested genetic predispositions by analyzing the family-specific variants in familial breast cancer. Using exome sequencing, we analyzed three families and 22 probands with BRCAx (BRCA-negative) familial breast cancer. RESULTS: We observed the presence of family-specific, novel, deleterious germline variants in each family. Of the germline variants identified, many were shared between the disease-affected family members of the same family but not found in different families, which have their own specific variants. Certain variants are putative deleterious genetic predispositions damaging functionally important genes involved in DNA replication and damaging repair, tumor suppression, signal transduction, and phosphorylation. CONCLUSIONS: Our study demonstrates that the predispositions for many BRCAx familial breast cancer families can lie in each disease family. The application of a family-focused approach has the potential to detect many new predispositions. BioMed Central 2014-06-26 /pmc/articles/PMC4083142/ /pubmed/24969172 http://dx.doi.org/10.1186/1471-2407-14-470 Text en Copyright © 2014 Wen et al.; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Wen, Hongxiu
Kim, Yeong C
Snyder, Carrie
Xiao, Fengxia
Fleissner, Elizabeth A
Becirovic, Dina
Luo, Jiangtao
Downs, Bradley
Sherman, Simon
Cowan, Kenneth H
Lynch, Henry T
Wang, San Ming
Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title_full Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title_fullStr Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title_full_unstemmed Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title_short Family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for BRCAx familial breast cancer
title_sort family-specific, novel, deleterious germline variants provide a rich resource to identify genetic predispositions for brcax familial breast cancer
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083142/
https://www.ncbi.nlm.nih.gov/pubmed/24969172
http://dx.doi.org/10.1186/1471-2407-14-470
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