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

我们分析了日本82个卵巢癌家系中BRCA1和BRCA2基因的遗传变化。采用直接测序的方法，在82个卵巢癌家系中发现45个携带BRCA1或BRCA2胚系突变(40个携带BRCA1，5个携带BRCA2)。在BRCA1的24个独立突变中，发现5个重复突变，其中T307A和C2919T突变分别在7个和8个独立家系中检测到。此外，BRCA1的18个突变和BRCA2的4个突变以前从未被描述过。BRCA1和BRCA2组肿瘤浆液性腺癌和晚期病例的比例明显高于对照组。另一方面，BRCA1或BRCA2突变患者的平均确诊年龄与对照组之间没有差异。我们的结果表明，BRCA1的T307A和C2919T突变似乎是日本人群特有的常见的方正突变。我们利用一组410个微卫星标记对28个BRCA1或BRCA2无突变的家系中的58名患者和9名未受影响的成员进行了全基因组连锁分析。我们最初使用GENEHUNTER程序通过非参数方法筛选了包括X染色体在内的整个基因组。结果表明，染色体3p22-25在D3S3611有一个连锁建议分数(LOD=3.49，NPL=2.77)。仅BRCA1或BRCA2基因无突变的患者肿瘤组织中LOH的发生率高于50%，而BRCA1基因突变患者肿瘤组织中该区域4种标志物的LOH发生率均不高于50%。

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.