Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors

BACKGROUND. BRCA-1 and BRCA-2 are tumor suppressor genes in familial breast -ovarian carcinoma syndrome. BRCA-1 is also a tumor suppressor gene in spor adic ovarian carcinomas. However, the role of BRCA-2 in sporadic ovarian tu mors remains unclear. METHODS. DNA from 52 patients with clinically apparent sporadic ovarian tum ors was extracted from blood and from fresh-frozen tumor tissue and normal tissue (10 benign, 7 borderline, and 35 malignant). Loss of heterozygosity (LOH) was analyzed in six micro satellite loci on chromosome 13q. BRCA-2 mu tations were detected by single-strand conformation polymorphism analysis a nd the protein truncation test. BRCA-2 promoter methylation was evaluated b y methylation specific polymerase chain reaction analysis. RESULTS. LOH on chromosome 13q12-q14 was identified in 16 tumors (30.8%): F ifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentia tion (12 of 16 tumors; 75%). LOH on chromosome 13q12-q14 coexisted with LOH on chromosome 17q in 10 carcinomas. BRCA-2 methylation was not detected in any tumor. BRCA-2 mutations were found in three tumors (one somatic nonsen se and two germline frameshift). BRCA-2 fulfilled the two hits for a tumor suppressor gene in these three tumors; in one of them, a BRCA-1 tumor suppr essor role had been demonstrated previously. CONCLUSIONS. The results suggest that BRCA-1 and BRCA-2 may act synergicall y in sporadic ovarian carcinomas with serous differentiation. The demonstra tion of BRCA-2 germline mutations in patients with ovarian carcinoma with L OH on chromosome 13q12-q14 and lack-of a remarkable family history of cance r suggest that the proportion of ovarian carcinomas that result from heredi tary predisposition may be higher than previously estimated. (C) 2001 Ameri can Cancer Society.