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Loss of heterozygosity on chromosome 13q12–q14, BRCA‐2 mutations and lack of BRCA‐2 promoter hypermethylation in sporadic epithelial ovarian tumors
Author(s) -
Gras Esther,
Cortes Joan,
Diez Orland,
Alonso Carmen,
MatiasGuiu Xavier,
Baiget Montserrat,
Prat Jaime
Publication year - 2001
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20010815)92:4<787::aid-cncr1384>3.0.co;2-4
Subject(s) - loss of heterozygosity , cancer research , serous fluid , tumor suppressor gene , ovarian carcinoma , ovarian cancer , ovarian tumor , germline mutation , biology , medicine , cancer , pathology , carcinogenesis , mutation , gene , genetics , allele
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 sporadic ovarian carcinomas. However, the role of BRCA‐2 in sporadic ovarian tumors remains unclear. METHODS DNA from 52 patients with clinically apparent sporadic ovarian tumors 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 microsatellite loci on chromosome 13q. BRCA‐2 mutations were detected by single‐strand conformation polymorphism analysis and the protein truncation test. BRCA‐2 promoter methylation was evaluated by methylation specific polymerase chain reaction analysis. RESULTS LOH on chromosome 13q12–q14 was identified in 16 tumors (30.8%): Fifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentiation (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 nonsense 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 suppressor role had been demonstrated previously. CONCLUSIONS The results suggest that BRCA‐1 and BRCA‐2 may act synergically in sporadic ovarian carcinomas with serous differentiation. The demonstration of BRCA‐2 germline mutations in patients with ovarian carcinoma with LOH on chromosome 13q12–q14 and lack of a remarkable family history of cancer suggest that the proportion of ovarian carcinomas that result from hereditary predisposition may be higher than previously estimated. Cancer 2001;92:787–95. © 2001 American Cancer Society.