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 Peixoto
  • Natália Salgueiro
  • Catarina Santos
  • Graça Varzim
  • Patrícia Rocha
  • Maria José Soares
  • Deolinda Pereira
  • Helena Rodrigues
  • Maria José Bento
  • António Fráguas
  • Graça Moura
  • Fernando Regateiro
  • Sérgio Castedo
  • Manuel R. Teixeira
Editorial Notes

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 

Abbreviations

BIC

The breast cancer information core

DGGE

Denaturing gradient gel electrophoresis

MLPA

Multiplex ligation-dependent probe amplification

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Copyright information

© Springer Science+Business Media B.V. 2006

Authors and Affiliations

  • Ana Peixoto
    • 1
  • Natália Salgueiro
    • 1
  • Catarina Santos
    • 1
  • Graça Varzim
    • 1
  • Patrícia Rocha
    • 1
  • Maria José Soares
    • 1
  • Deolinda Pereira
    • 2
  • Helena Rodrigues
    • 2
  • Maria José Bento
    • 3
  • António Fráguas
    • 4
  • Graça Moura
    • 5
  • Fernando Regateiro
    • 6
  • Sérgio Castedo
    • 1
  • Manuel R. Teixeira
    • 1
  1. 1.Department of GeneticsPortuguese Oncology InstitutePortoPortugal
  2. 2.Departments of OncologyPortuguese Oncology InstitutePortoPortugal
  3. 3.Departments of EpidemiologyPortuguese Oncology InstitutePortoPortugal
  4. 4.Espírito Santo HospitalÉvoraPortugal
  5. 5.St. António General HospitalPortoPortugal
  6. 6.Coimbra University HospitalCoimbraPortugal

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