Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14

Breast Cancer Res Treat. 2014 Dec;148(3):629-35. doi: 10.1007/s10549-014-3196-z. Epub 2014 Nov 14.

Abstract

Hereditary breast and ovarian cancer are mainly linked to mutations in BRCA1 and BRCA2 genes which confer a similar cumulative risk of developing breast cancer. Importantly, while BRCA2 mutation carriers generally have a lower cumulative risk for ovarian cancer, mutations clustered in the central portion of BRCA2 are associated with a higher proportion of ovarian compared with breast cancer cases. The boundaries of this ovarian cancer cluster region (OCCR) have been tentatively defined within a 3.3 kb region of BRCA2 exon 11, and herein, we reassessed these boundaries using our series of Italian breast/ovarian cancer families. We used direct sequencing to investigate BRCA mutations in 367 breast/ovarian cancer families. We also studied the association between the location of the mutations and the ovarian cancer phenotype in our cohort of BRCA2-mutated families. We observed the novel c.7309_7309delA frameshift mutation and the c.7007G>A deleterious mutation in BRCA2 exons 14 and 13, respectively, in five independent Italian families characterized by a high proportion of ovarian cancer cases. Of note, a significantly higher proportion of ovarian versus breast cancer cases was associated not only with mutations in the previously defined OCCR (OR = 5.91; p = 0.004), but also with the exon 13-14 region (OR = 7.37; p = 0.001) in our BRCA2-mutated families. Our data provide initial evidence for a novel putative OCCR in BRCA2 exons 13-14.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • BRCA2 Protein / genetics*
  • Breast Neoplasms / epidemiology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Breast Neoplasms, Male / epidemiology
  • Breast Neoplasms, Male / genetics*
  • Exons
  • Female
  • Germ-Line Mutation
  • Humans
  • Italien
  • Male
  • Middle Aged
  • Mutation
  • Ovarian Neoplasms / epidemiology
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / pathology
  • Pedigree

Substances

  • BRCA2 Protein
  • BRCA2 protein, human

Supplementary concepts

  • Breast Cancer, Familial