ABSTRACT
Susceptibility genes include BRCA1 (20-40% of hereditary breast cancers), BRCA2 (10-30%), TP53 (<1%), PTEN (<1%), ATM , CHK2 , STK11 (<1%), and Fanconi’s Anemia genes (1%) (5). BRCA1 and BRCA2 are associated with hereditary breast cancer in younger age groups, increased incidence of familial ovarian cancer ( BRCA1 and BRCA2 ), and male breast cancer ( BRCA2 ). The lifetime breast cancer risk among women with BRCA1/2 varies from 56% to 80-85% (6). Several mutations in BRCA1/2 occur with a higher frequency among individuals of Ashkenazi (East European) Jewish descent, with three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) accounting for the majority of germline mutations (7). A two-hit model has been proposed to explain the mechanism by which breast cancer can arise in BRCA1/2 carriers. The first hit represents loss of the wild type BRCA1 or BRCA2 allele, resulting in an increased rate for subsequent genomic events. A second event increasing proliferation of the partially malignant clone may lead to selection of cells with additional mutations in genes that facilitate tumor progression (8). BRCA1-related breast cancer features include earlier age at onset, medullary features, higher proliferation, poor differentiation, estrogen receptor (ER) and progesterone receptor (PR) negative, HER-2-negative, EGFR-positive, often with basal-like phenotype, and more lymphocytic infiltration than sporadic cancers. BRCA2-related breast cancer features include lower mitotic counts and expression of ER/PR. Despite the association with adverse prognostic characteristics, BRCA1/ 2-associated breast cancers have prognoses similar to or better than sporadic tumors of similar stage (9).
