MUTATIONAL ANALYSIS OF BRCA1 GENE IN OVARIAN AND BREAST-OVARIAN CANCER FAMILIES IN JAPAN

We analyzed the alteration of BRCA1 in DNA obtained from 83 individual s of 13 Japanese site-specific ovarian cancer families and 6 breast-ov arian cancer families. Six germline mutations were detected in 7 famil ies, which consisted of 4 breast ovarian cancer and 3 site-specific ov arian cancer families, by single-strand conformation polymorphism anal ysis, followed by direct sequence determination. The mutations include d three frameshifts, two nonsense mutations, and one missense mutation causing loss of a zinc-binding motif. The frequency of loss of hetero zygosity at the microsatellite markers on the BRCA1 gene was 57% (8 of 14 cases) in site-specific ovarian cancer families, and 100% (6 of 6 cases) in breast-ovarian cancer families. Ail tumors of the patients c arrying a mutation of BRCA1 showed deletion of wild-type alleles, impl icating BRCA1 as a tumor suppressor gene. These results suggest that g ermline mutations of the BRCA1 gene play an important role in the carc inogenesis of breast and/or ovarian cancer in a majority of breast-ova rian cancer families and in some site-specific ovarian cancer families .