Relationship of BRCA1 and BRCA2 mutations with cancer burden in the family and tumor incidence

The aim of the present study is to analyze the relationship of the incidence of mutations in the two major genes BRCA1 and BRCA2 conferring risk of breast cancer (BC) and ovarian cancer (OC) with the cancer burden in families and with the presence and age of onset of BC/OC. We included 704 index patients (IP) and 668 family members of the IP who tested positive for BRCA1/BRCA2 who were studied in the Program of Genetic Counselling in Cancer of the Valencia Community (Spain). We found 129 IPs with deleterious mutations (18.3%), 59 in BRCA1 and 70 in BRCA2, detecting 396 mutations in this kindred. The incidence of mutations and their distribution between BRCA1 and BRCA2 showed a significantly uneven incidence among the family groups (P < 0.001). We found 179 tumors in the 396 mutation carriers (45%) and detected only 11 cancers among the 272 non-mutation carriers (P < 0.001). No differences in the tumor prevalence or the age of onset of cancer between the genes among the mutation carriers were found. The mutation carriers showed a 50% probability of having BC/OC at a median age of 49 years (95% CI 46–52 years) and 78% at the age of 70 years (95% CI: 71–85%). In conclusion the family burden of BC and OC is strongly associated with the incidence of BRCAs mutations and could foretell which of the two BRCAs genes is more likely to have mutations. Mutation carriers have a 50% risk of having BC/OC by the age of 50 years.