BRCA1 and BRCA2 mutations in ovarian cancer: Covariation with specific cytogenetic features

We analyzed 37 primary invasive carcinomas for BRCA1 and BRCA2 mutations by screening the entire coding regions of both genes. Seven predicted truncat ing mutations (four in BRCA1 and three in BRCA2) and one novel BRCA1 missen se variant (S1542C) were identified (8/37, 22%). Two of the BRCA1 mutations were somatic changes, whereas the remaining three BRCA1 changes and all mu tations of BRCA2 were found to be of germline origin. All eight BRCA-positi ve tumors were serous or seropapillary carcinomas (8/27 serous tumors, 30%) , and all but one were poorly differentiated. The correlation between tumor karyotype and BRCA status showed that clonal chromosomal aberrations were present in all BRCA-positive tumors (8/8) compared with 20 of 29 BRCA-negat ive ones. The most consistently affected region in BRCA-positive tumors was the long arm of chromosome 6; alterations within this arm with a breakpoin t in band 6q21 were seen in four of five BRCA1-positive and in two of three BRCA2-positive tumors, but only in four of 20 karyotypically abnormal tumo rs without BRCA mutations, suggesting that the genetic pathways of tumor pr ogression differ in the two groups. The high frequency of germline BRCA mut ations detected in this pilot study (16% of 37 invasive carcinomas) points to the need for more extended analyses of population-based series of patien ts to determine the true contribution of these predisposing genes to the ov erall incidence of ovarian cancer in this population.