The isolation and characterization of novel susceptibility gene for familial ovarian cancer.

点击翻译按钮获取中文摘要

We analyzed genetic alterations in BRCA1 and BRCA2 genes among 82 ovarian cancer families in Japan. Using a direct sequencing method, 45 out of the 82 ovarian cancer families were found to carry BRCA1 or BRCA2 germline mutations (40 with BRCA1 and 5 with BRCA2). In 24 independent mutations of BRCA1, five recurrent mutations were found and two of them, the T307A and C2919T mutations, were detected in 7 and 8 independent families, respectively. In addition, 18 mutations of BRCA1 and 4 mutations of BRCA2 have never been described previously. There was a significantly higher proportion of tumors with serous adenocarcinoma and of cases of advanced stages in the BRCA1 or BRCA2 cases than those of the controls. On the other hand, there were no differences of mean age at diagnosis between patients with BRCA1 or BRCA2 mutation and those of the controls. Our results indicate that the T307A and C2919T mutations of BRCA1 appear to be common founder mutations unique to the Japanese population. We performed genome-wide linkage analysis in 58 patients and 9 unaffected members among 28 families with no mutation in BRCA1 or BRCA2 employing a set of 410 microsatellite markers. We initially screened the whole genome including the X-chromosome by a nonparametric method using the GENEHUNTER program. As a result, chromosome 3p22-25 showed a suggestive score for linkage (LOD = 3.49 and NPL = 2.77 at D3S3611) based on a multipoint analysis. It was observed that the frequency of LOH was more than 50% only in tumor tissues from patients with no mutation in BRCA1 or BRCA2 but not in those with BRCA1 mutation at 4 markers in this region.