The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer.
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.
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Sofia
S
Maia
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Marta
M
Cardoso
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Paula
P
Paulo
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Manuela
M
Pinheiro
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Pedro
P
Pinto
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Catarina
C
Santos
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Carla
C
Pinto
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Ana
A
Peixoto
Department of Pathology, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|Cancer Biology and Epigenetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.|Biomedical Sciences Institute (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313, Porto, Portugal.
Rui
R
Henrique
Department of Genetics and Cancer Genetics Group - CI-IPOP, Portuguese Oncology Institute - Porto, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal. manuel.teixeira@ipoporto.min-saude.pt.|Biomedical Sciences Institute (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313, Porto, Portugal. manuel.teixeira@ipoporto.min-saude.pt.
Manuel R
MR
Teixeira
D000328:Adult; D017668:Age of Onset; D053843:DNA Mismatch Repair / Q000235:genetics*; D004252:DNA Mutational Analysis; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics*
BRCA1; BRCA2; Founder mutations; Hereditary cancer predisposition; Mismatch repair genes; Prostate cancer