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The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer

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Abstract

Prostate cancer (PrCa) is one of the most common cancers diagnosed worldwide and 5–10 % of all cases are estimated to be associated with inherited predisposition. Even though there is strong evidence that the genetic component is significant in PrCa, the genetic etiology of familial and early-onset disease is largely unknown. Although it has been suggested that men from families with hereditary breast/ovarian cancer (HBOC) and, more recently, with Lynch syndrome may have an increased risk for PrCa, the contribution of these syndromes to PrCa predisposition in families ascertained for early-onset and/or familial PrCa, independently of the presence of other cancers in the family, is uncertain. To quantify the contribution of genes associated with HBOC and Lynch syndromes to PrCa predisposition, we have tested for germline mutations 460 early-onset and/or familial PrCa patients. All patients were screened for the six mutations that are particularly common in Portugal and 38 of them were selected for complete sequencing of BRCA1/2 and/or MLH1, MSH2 and MSH6. Two patients were found to harbor the same MSH2 mutation and a third patient carried a Portuguese BRCA2 founder mutation. None of the alterations were identified in 288 control subjects. Furthermore, we reviewed the 62 PrCa diagnoses in all HBOC (n = 161) and Lynch syndrome (n = 124) families previously diagnosed at our department, and found five other BRCA2 mutation carriers and two additional MSH2 mutation carriers. The clinicopathological characteristics of mutation carriers are in concordance with earlier data suggesting an aggressive PrCa phenotype and support the hypothesis that mutation carriers might benefit from targeted screening according to the gene mutated in the germline.

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Acknowledgments

We would like to thank Professor Michael Griffiths from the West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, United Kingdom for having kindly provided us the primers and PCR conditions for Sanger sequencing of the BRCA1/2 and MMR genes. We deeply appreciate the participation of patients and their families in this study. SM and PPi were awarded PhD Grants (SFRH/BD/71397/2010 and SFRH/BD/73719/2010, respectively) by the Portuguese Foundation for Science and Technology (www.fct.pt/index.phtml.en). MC, MP and PPa are recipients of research scholarships awarded by Portuguese Cancer Association (www.ligacontracancro.pt). The project was also funded by the Portuguese Oncology Institute-Porto (www.ipoporto.pt/en/; Grant Reference: CI-IPOP 16-2012) and by strategic funding of the Portuguese Foundation for Science and Technology (UID/DTP/00776/2013).

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Authors and Affiliations

  1. Department of Genetics and Cancer Genetics Group – CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Sofia Maia, Marta Cardoso, Paula Paulo, Manuela Pinheiro, Pedro Pinto, Catarina Santos, Carla Pinto, Ana Peixoto & Manuel R. Teixeira

  2. Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Rui Henrique

  3. Cancer Biology and Epigenetics Group – CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Rui Henrique

  4. Biomedical Sciences Institute (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313, Porto, Portugal

    Rui Henrique & Manuel R. Teixeira

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  1. Sofia Maia
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  2. Marta Cardoso
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  3. Paula Paulo
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Correspondence to Manuel R. Teixeira.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Institutional Ethics Committee of the Portuguese Oncology Institute-Porto, approval number: 38.010) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Maia, S., Cardoso, M., Paulo, P. et al. The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer. Familial Cancer 15, 111–121 (2016). https://doi.org/10.1007/s10689-015-9832-x

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