BRCA1 and BRCA2 hereditary breast carcinoma phenotypes

BACKGROUND. Mutations in two major susceptibility genes, BRCAI and BRCA2, account for most hereditary breast carcinoma (HBC). METHODS. BRCAI and BRCA2 genotype-phenotype associations are reviewed with special emphasis on pathologic characteristics. Tumor spectra in families, prognosis phenotype, and molecular biologic correlates with phenotype are also explored. RESULTS. BRCAI is an estrogen-inducable cell cycle-associated protein with anti-proliferation and tumor suppressor function. Less is known about BRCA2 protein but it has some similarities to BRCA1. Release of cells from BRCA1 control through germline mutations gives rise to genetically evolved breast carcinomas with a highly distinctive and correspondent proliferator phenotype featuring aneuploidy, high S-phase fraction, high mitotic grade, and medullary carcinomas. BRCA1 HBCs also show a deficit of ductal carcinoma in situ and invasive lobular, tubular, tubulolobular, and cribriform (tubular-lobular group [TLG]) carcinomas. In contrast, the BRCA2 HBC phenotype, although less well determined and possibly more heterogeneous, appears to lack the more extensive BRCA1 proliferator characteristics but may have excess TLG carcinomas. Despite their adverse pathoprognostic features, BRCAI HBCs have paradoxically better disease free survivals than non-BRCA1 HBCs, but data are not yet clear whether this effect can be attributed to BRCA2 HBC generally. Larger studies are needed to assess potential heterogeneity. CONCLUSIONS. Although the phenotypes are presently imperfectly resolved, early studies indicate differences between BRCAI and BRCA2 HBC.