FREQUENCY OF GERMLINE AND SOMATIC BRCA1 MUTATIONS IN OVARIAN-CANCER

Germline mutations in the BRCA1 tumor suppressor gene are thought to b e the most common cause of hereditary ovarian cancer. The aim of this study was to explore further the role of BRCA1 alterations in the deve lopment of ovarian cancers. We sought to determine whether somatic BRC A1 mutations are ever present in ovarian cancers and whether mutation is always accompanied by loss of the wild-type allele, The entire codi ng region and intronic splice sites of BRCA1 were sequenced using geno mic DNA samples from 103 unselected ovarian cancers. Thirteen clearly deleterious BRCA1 mutations and two variants of uncertain significance were found, Blood DNA was available in all but two cases and demonstr ated that 4 of 13 mutations and both variants of uncertain significanc e were germline alterations, whereas in seven cases the mutation was a somatic change present only in the cancer, Using four microsatellite markers, loss of heterozygosity at the BRCA1 locus was found in all 15 ovarian cancers with BRCA1 sequence alterations, compared with only 5 8% of ovarian cancers that did not have BRCA1 mutations. BRCA1-associa ted ovarian cancers were characterized by serous histology and moderat e histological grade. These data confirm prior reports suggesting that germline mutations in BRCA1 are present in about 5% of women with ova rian cancer. In addition, somatic mutations in BRCA1 occur in the deve lopment of some sporadic cases. The finding that both germline and som atic BRCA1 mutations are accompanied by loss of heterozygosity, sugges ts that loss of this tumor suppressor gene is a critical event in the development of these cancers.