Mutational Analysis of BRCA1 Gene in Ovarian and Breast‐ovarian Cancer Families in Japan

We analyzed the alteration of BRCAI in DNA obtained from 83 individuals of 13 Japanese site‐specific ovarian cancer families and 6 breast‐ovarian cancer families. Six germline mutations were detected in 7 families, which consisted of 4 breast‐ovarian cancer and 3 site‐specific ovarian cancer families, by single‐strand conformation polymorphism analysis, followed by direct sequence determination. The mutations included three framcshifts, two nonsense mutations, and one missense mutation causing loss of a zinc‐binding motif. The frequency of loss of heterozygosity at the microsatellite markers on the BRCAI gene was 57% (8 of 14 cases) in site‐specific ovarian cancer families, and 100% (6 of 6 cases) in breast‐ovarian cancer families. All tumors of the patients carrying a mutation of BRCAI showed deletion of wild‐type alleles, implicating BRCAI as a tumor suppressor gene. Tbese results suggest tbat germline mutations of the BRCAI gene play an important role in the carcinogen‐esis of breast and/or ovarian cancer in a majority of breast‐ovarian cancer families and in some site‐specific ovarian cancer families.