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

Francisco Javier Gracia-Aznarez, Victoria Fernandez, Guillermo Pita, Paolo Peterlongo, Orlando Dominguez, Miguel de la Hoya, Mercedes Duran, Ana Osorio, Leticia Moreno, Anna Gonzalez-Neira, Juan Manuel Rosa-Rosa, Olga Sinilnikova, Sylvie Mazoyer, John Hopper, Conchi Lazaro, Melissa Southey, Fabrice Odefrey, Siranoush Manoukian, Irene Catucci, Trinidad Caldes & 8 others Henry T. Lynch, Florentine S M Hilbers, Christi J. van Asperen, Hans F A Vasen, David Goldgar, Paolo Radice, Peter Devilee, Javier Benitez

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere55681
JournalPLoS One
Volume8
Issue number2
DOIs
StatePublished - Feb 8 2013

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Exome
penetrance
Penetrance
breast neoplasms
Genes
Alleles
Breast Neoplasms
alleles
genes
Cell proliferation
Automatic teller machines
High-Throughput Nucleotide Sequencing
Assays
DNA repair
Repair
DNA Repair
Cells
Throughput
Association reactions
cell viability

All Science Journal Classification (ASJC) codes

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Gracia-Aznarez, F. J., Fernandez, V., Pita, G., Peterlongo, P., Dominguez, O., de la Hoya, M., ... Benitez, J. (2013). Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles. PLoS One, 8(2), [e55681]. https://doi.org/10.1371/journal.pone.0055681

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.

In: PLoS One, Vol. 8, No. 2, e55681, 08.02.2013.

Research output: Contribution to journalArticle

Gracia-Aznarez, FJ, Fernandez, V, Pita, G, Peterlongo, P, Dominguez, O, de la Hoya, M, Duran, M, Osorio, A, Moreno, L, Gonzalez-Neira, A, Rosa-Rosa, JM, Sinilnikova, O, Mazoyer, S, Hopper, J, Lazaro, C, Southey, M, Odefrey, F, Manoukian, S, Catucci, I, Caldes, T, Lynch, HT, Hilbers, FSM, van Asperen, CJ, Vasen, HFA, Goldgar, D, Radice, P, Devilee, P & Benitez, J 2013, 'Whole Exome Sequencing Suggests Much of Non-BRCA1/BRCA2 Familial Breast Cancer Is Due to Moderate and Low Penetrance Susceptibility Alleles', PLoS One, vol. 8, no. 2, e55681. https://doi.org/10.1371/journal.pone.0055681
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. In: PLoS One. 2013 ; Vol. 8, No. 2.
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abstract = "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.",
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AU - Gracia-Aznarez, Francisco Javier

AU - Fernandez, Victoria

AU - Pita, Guillermo

AU - Peterlongo, Paolo

AU - Dominguez, Orlando

AU - de la Hoya, Miguel

AU - Duran, Mercedes

AU - Osorio, Ana

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AU - Odefrey, Fabrice

AU - Manoukian, Siranoush

AU - Catucci, Irene

AU - Caldes, Trinidad

AU - Lynch, Henry T.

AU - Hilbers, Florentine S M

AU - van Asperen, Christi J.

AU - Vasen, Hans F A

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AU - Radice, Paolo

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AU - Benitez, Javier

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