Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles

The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in bre...

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Main Authors:	Gracia-Aznarez, Francisco Javier, Fernandez, Victoria, Pita, Guillermo, Peterlongo, Paolo, Dominguez, Orlando, de la Hoya, Miguel, Duran, Mercedes, Osorio, Ana, Moreno, Leticia, Gonzalez-Neira, Anna, Rosa-Rosa, Juan Manuel, Sinilnikova, Olga, Mazoyer, Sylvie, Hopper, John, Lazaro, Conchi, Southey, Melissa, Odefrey, Fabrice, Manoukian, Siranoush, Catucci, Irene, Caldes, Trinidad, Lynch, Henry T., Hilbers, Florentine S. M., van Asperen, Christi J., Vasen, Hans F. A., Goldgar, David, Radice, Paolo, Devilee, Peter, Benitez, Javier
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568132/

id	pubmed-3568132
recordtype	oai_dc
spelling	pubmed-35681322013-02-13 Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles Gracia-Aznarez, Francisco Javier Fernandez, Victoria Pita, Guillermo Peterlongo, Paolo Dominguez, Orlando de la Hoya, Miguel Duran, Mercedes Osorio, Ana Moreno, Leticia Gonzalez-Neira, Anna Rosa-Rosa, Juan Manuel Sinilnikova, Olga Mazoyer, Sylvie Hopper, John Lazaro, Conchi Southey, Melissa Odefrey, Fabrice Manoukian, Siranoush Catucci, Irene Caldes, Trinidad Lynch, Henry T. Hilbers, Florentine S. M. van Asperen, Christi J. Vasen, Hans F. A. Goldgar, David Radice, Paolo Devilee, Peter Benitez, Javier Research Article The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles. Public Library of Science 2013-02-08 /pmc/articles/PMC3568132/ /pubmed/23409019 http://dx.doi.org/10.1371/journal.pone.0055681 Text en © 2013 Gracia-Aznarez et al http://creativecommons.org/licenses/by/4.0/ 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 properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Gracia-Aznarez, Francisco Javier Fernandez, Victoria Pita, Guillermo Peterlongo, Paolo Dominguez, Orlando de la Hoya, Miguel Duran, Mercedes Osorio, Ana Moreno, Leticia Gonzalez-Neira, Anna Rosa-Rosa, Juan Manuel Sinilnikova, Olga Mazoyer, Sylvie Hopper, John Lazaro, Conchi Southey, Melissa Odefrey, Fabrice Manoukian, Siranoush Catucci, Irene Caldes, Trinidad Lynch, Henry T. Hilbers, Florentine S. M. van Asperen, Christi J. Vasen, Hans F. A. Goldgar, David Radice, Paolo Devilee, Peter Benitez, Javier
spellingShingle	Gracia-Aznarez, Francisco Javier Fernandez, Victoria Pita, Guillermo Peterlongo, Paolo Dominguez, Orlando de la Hoya, Miguel Duran, Mercedes Osorio, Ana Moreno, Leticia Gonzalez-Neira, Anna Rosa-Rosa, Juan Manuel Sinilnikova, Olga Mazoyer, Sylvie Hopper, John Lazaro, Conchi Southey, Melissa Odefrey, Fabrice Manoukian, Siranoush Catucci, Irene Caldes, Trinidad Lynch, Henry T. Hilbers, Florentine S. M. van Asperen, Christi J. Vasen, Hans F. A. Goldgar, David Radice, Paolo Devilee, Peter Benitez, Javier Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
author_facet	Gracia-Aznarez, Francisco Javier Fernandez, Victoria Pita, Guillermo Peterlongo, Paolo Dominguez, Orlando de la Hoya, Miguel Duran, Mercedes Osorio, Ana Moreno, Leticia Gonzalez-Neira, Anna Rosa-Rosa, Juan Manuel Sinilnikova, Olga Mazoyer, Sylvie Hopper, John Lazaro, Conchi Southey, Melissa Odefrey, Fabrice Manoukian, Siranoush Catucci, Irene Caldes, Trinidad Lynch, Henry T. Hilbers, Florentine S. M. van Asperen, Christi J. Vasen, Hans F. A. Goldgar, David Radice, Paolo Devilee, Peter Benitez, Javier
author_sort	Gracia-Aznarez, Francisco Javier
title	Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
title_short	Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
title_full	Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
title_fullStr	Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
title_full_unstemmed	Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles
title_sort	whole exome sequencing suggests much of non-brca1/brca2 familial breast cancer is due to moderate and low penetrance susceptibility alleles
description	The identification of the two most prevalent susceptibility genes in breast cancer, BRCA1 and BRCA2, was the beginning of a sustained effort to uncover new genes explaining the missing heritability in this disease. Today, additional high, moderate and low penetrance genes have been identified in breast cancer, such as P53, PTEN, STK11, PALB2 or ATM, globally accounting for around 35 percent of the familial cases. In the present study we used massively parallel sequencing to analyze 7 BRCA1/BRCA2 negative families, each having at least 6 affected women with breast cancer (between 6 and 10) diagnosed under the age of 60 across generations. After extensive filtering, Sanger sequencing validation and co-segregation studies, variants were prioritized through either control-population studies, including up to 750 healthy individuals, or case-control assays comprising approximately 5300 samples. As a result, a known moderate susceptibility indel variant (CHEK2 1100delC) and a catalogue of 11 rare variants presenting signs of association with breast cancer were identified. All the affected genes are involved in important cellular mechanisms like DNA repair, cell proliferation and survival or cell cycle regulation. This study highlights the need to investigate the role of rare variants in familial cancer development by means of novel high throughput analysis strategies optimized for genetically heterogeneous scenarios. Even considering the intrinsic limitations of exome resequencing studies, our findings support the hypothesis that the majority of non-BRCA1/BRCA2 breast cancer families might be explained by the action of moderate and/or low penetrance susceptibility alleles.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3568132/
_version_	1611953637002575872

Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles

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