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Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity

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Abstract

Molecular diagnosis of hereditary breast and ovarian cancer (HBOC) by standard methodologies has been limited to the BRCA1 and BRCA2 genes. With the recent development of new sequencing methodologies, the speed and efficiency of DNA testing have dramatically improved. The aim of this work was to validate the use of next-generation sequencing (NGS) for the detection of BRCA1/BRCA2 point mutations in a diagnostic setting and to study the role of other genes associated with HBOC in Portuguese families. A cohort of 94 high-risk families was included in the study, and they were initially screened for the two common founder mutations with variant-specific methods. Fourteen index patients were shown to carry the Portuguese founder mutation BRCA2 c.156_157insAlu, and the remaining 80 were analyzed in parallel by Sanger sequencing for the BRCA1/BRCA2 genes and by NGS for a panel of 17 genes that have been described as involved in predisposition to breast and/or ovarian cancer. A total of 506 variants in the BRCA1/BRCA2 genes were detected by both methodologies, with a 100 % concordance between them. This strategy allowed the detection of a total of 39 deleterious mutations in the 94 index patients, namely 10 in BRCA1 (25.6 %), 21 in BRCA2 (53.8 %), four in PALB2 (10.3 %), two in ATM (5.1 %), one in CHEK2 (2.6 %), and one in TP53 (2.6 %), with 20.5 % of the deleterious mutations being found in genes other than BRCA1/BRCA2. These results demonstrate the efficiency of NGS for the detection of BRCA1/BRCA2 point mutations and highlight the genetic heterogeneity of HBOC.

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Acknowledgments

We would like to thank everyone involved in the TVI Solidary fundraising event, namely organizers, singers, and participants.

Funding

This work was partially supported by IPO Porto Research Center (CI-IPOP-16-2012), by the Portuguese television broadcasting channel TVI (Solidary fundraising event), and by Fundação para a Ciência e a Tecnologia (FCT; PEst-OE/SAU/UI0776/2014). PP was awarded a PhD grant (SFRH/BD/73719/2010) from FCT until 2015. PPa and MP are research fellows from FCT (UID/DTP/00776/2013 and SFRH/BPD/113014/2015). PP is a research fellow of the Núcleo Regional do Norte da Liga Portuguesa Contra o Cancro.

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Authors and Affiliations

  1. Cancer Genetics Group, IPO Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto), Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Pedro Pinto, Paula Paulo, Manuela Pinheiro & Manuel R. Teixeira

  2. Department of Genetics, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal

    Catarina Santos, Patrícia Rocha, Carla Pinto, Isabel Veiga, Ana Peixoto & Manuel R. Teixeira

  3. Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal

    Manuel R. Teixeira

Authors
  1. Pedro Pinto
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  2. Paula Paulo
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  3. Catarina Santos
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  4. Patrícia Rocha
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  5. Carla Pinto
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  6. Isabel Veiga
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  7. Manuela Pinheiro
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  8. Ana Peixoto
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  9. Manuel R. Teixeira
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Corresponding author

Correspondence to Manuel R. Teixeira.

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The authors declare no conflicts of interest.

Ethical standards

This study was performed according to the institutional review board approved guidelines and standard clinical practice, and informed consent was obtained from all individual participants included in the study.

Electronic supplementary material

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10549_2016_3948_MOESM1_ESM.tif

Supplementary material 1 (TIFF 460 kb) Pedigree of the individual with the MSH6 c.3848_3862del mutation. The index case is indicated by an arrow

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Pinto, P., Paulo, P., Santos, C. et al. Implementation of next-generation sequencing for molecular diagnosis of hereditary breast and ovarian cancer highlights its genetic heterogeneity. Breast Cancer Res Treat 159, 245–256 (2016). https://doi.org/10.1007/s10549-016-3948-z

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  • DOI: https://doi.org/10.1007/s10549-016-3948-z

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