The molecular pathology of hereditary breast cancer

Hereditary breast cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer and from non-BRCA1/2 familial breast carcinomas. Most BRCA1 carcinomas have the basal-like phenotype and are high-grade, highly proliferating, estrogen receptor-negative and HER2-negative breast carcinomas, characterized by the expression of basal markers such as basal keratins, P-cadherin and epidermal growth factor receptor. BRCA1 carcinomas frequently carry p53 mutations. The basal-like phenotype is only occasionally found in BRCA2 carcinomas, which tend to be estrogen and progesterone receptor positive. BRCA1 and BRCA2 loss of heterozygosity is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Both genotypes have a low frequency of HER2 expression/amplification. In addition, comparative genomic hybridization and array expression studies have revealed differences in chromosomal gains and losses as well as expression patterns between genotypes. Several studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations are heterogeneous and have phenotypic similarities to BRCA2 tumors. A small group of cases are secondary to mutations in other breast cancer susceptibility genes, such as p53, PTEN or CDH1. As a result of the low frequency of breast carcinomas attributable to mutations in these genes, it is very difficult to establish a specific phenotype for each genotype, other than the association of lobular carcinomas with CDH1 germline mutations. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening.