THe genetics of familial breast cancer

Because studies of breast cancer patients and their relatives provide statistical evidence for involvement of autosomal dominant genes, the identification of specific genetic effects has long been the focus of efforts to identify women at exceedingly high risk. BRCA1, a gene that confers greatly increased susceptibility to breast and ovarian cancer, was isolated in 1994, capping an intense analysis by a large number of groups of a complex phenotype. BRCA1 is a large gene and shows only limited homology to other known genes. Near the amino terminus of the predicted protein is a RING finger motif. In addition, a leucine heptad repeat appears in the interior of the sequence. Several groups have looked extensively for somatic BRCAI mutations in breast and ovarian tumors. The frequency of somatic mutations in ovarian tumors is low, and to date no somatic mutations have been found in breast tumors. More research is needed to define the role of BRCA1 in sporadic tumors. A second locus associated with predisposition to early onset breast cancer, BRCA2, has been localized to chromosome 13q. Positional cloning of this gene is well advanced and analysis of its biology and mutation spectrum is eagerly awaited. As the BRCA1 and BRCA2 genes are characterized further, a diagnostic test for breast cancer susceptibility becomes feasible.