Pathology of BRCA tumors

Abstract

Hereditary or familial breast cancer is defined as breast cancers affecting several family members and involving different generations. An estimated 5% of all breast cancers are associated with a germline mutation in the high-penetrance genes BRCA1 and BRCA2 located in chromosomes 17q21 and 13q12.3, respectively. BRCA-mutated cancers are more frequently seen in women younger than age 40. In addition to breast cancer, BRCA1is associated with ovarian cancer. BRCA1 breast-associated tumors are mostly invasive ductal carcinomas, and they tend to be of high grade, with high proliferative rates, and pushing borders. By immunohistochemistry, they tend to be triple-negative (estrogen receptor alpha, progesterone receptor, and Her2neu-negative) and p53-positive and express basal markers (CK5/6, CK14, EGFR, caveolin-1, vimentin, laminin, p-cadherin, etc.). There is a high incidence of medullary carcinomas among young patients with BRCA1 cancers. BRCA2-associated tumors are mostly invasive ductal carcinomas not otherwise specified (NOS) or no special type (NST), moderate to high grade, with pushing borders. The immunophenotype of BRCA2 tumors is similar to sporadic breast cancers and are frequently estrogen receptor alpha and progesterone receptor-positive as well as negative for Her2neu. An increase incidence of lobular carcinoma, including pleomorphic lobular carcinoma, has been reported in BRCA2 carriers. BRCA2 tumors express luminal markers (CK8, CK18) and do not express the basal markers seen in BRCA1 cancers. BRCA2 carriers are also at risk of prostate, pancreatic, ovarian, and fallopian tube cancers and melanoma. Hereditary but non-BRCA1/2-mutated breast cancers have some similarities to BRCA2 cancers. Other high-risk genes associated with hereditary breast cancer include PTEN, TP53, STK1/LKB1, CDH1, CHEK2, ATM, NBS1, RAD50, BRIP1,and PALB2. There is little information on these genes and will be only mentioned briefly. Most of these genes confer a low risk. Li-Fraumeni syndrome (TP53 gene) and Cowden's syndrome (PTEN gene) are associated with a high risk of breast cancer; they however account for a very small number of breast cancers. Most of the hereditary breast cancers are associated with BRCA1 and BRCA2.