Editorial Notes

Familial Cancer

, Volume 5, Issue 4, pp 379-387

BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families

  • Ana PeixotoAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Natália SalgueiroAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Catarina SantosAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Graça VarzimAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Patrícia RochaAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Maria José SoaresAffiliated withDepartment of Genetics, Portuguese Oncology Institute
  • , Deolinda PereiraAffiliated withDepartments of Oncology, Portuguese Oncology Institute
  • , Helena RodriguesAffiliated withDepartments of Oncology, Portuguese Oncology Institute
  • , Maria José BentoAffiliated withDepartments of Epidemiology, Portuguese Oncology Institute
    • , António FráguasAffiliated withEspírito Santo Hospital
    • , Graça MouraAffiliated withSt. António General Hospital
    • , Fernando RegateiroAffiliated withCoimbra University Hospital
    • , Sérgio CastedoAffiliated withDepartment of Genetics, Portuguese Oncology Institute
    • , Manuel R. TeixeiraAffiliated withDepartment of Genetics, Portuguese Oncology Institute Email author 

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Abstract

We present the first characterisation of the mutational spectrum of the entire coding sequences and exon–intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11–15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

Keywords

BRCA1 BRCA2 Breast/ovarian cancer families Genetic anticipation Germline mutations