Mutation unalysis of the BRCA1 gene in familial and sporudic breast cancer

家族性和散发性乳腺癌BRCA1基因突变分析

基本信息

批准号：
07457264
负责人：
EMI Mitsuru
金额：
$ 0.83万
依托单位：
Nippon Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457264/
关键词：
Breast Cancer ovarian cancer BRCA 1 SSCP mutation presymptomitic dingnosis SScP法

项目摘要

Predisposing mutations in a BRCA1 gene have been recently identified in 17-9 linked breast and ovarian cancer families. We examined breast cancers consisting of 46 early-onse cases (<35 of age), 12 cases with familial clustering, and 59 bilateral cancers for mutations ir entire coding exons of BRCA1 gene using single strand conformation polymorphism (SSCP) analysis. Four mutaions were detected in this panel of 103 patients ; a flame-shift due to 2-bp deletion at codon 797, a nonsense mutation at codon 1214, two missense mutations, one at codon 271 leading to Val->Met substitution, and the other at codon 1150 leading to Pro->Ser substitution. All of them were germiline mutations ; no somatic mutation were found in these tumors, a finding that support a rather confined role of BRCA1 in breast carcinogenesis. Among the three selection groups, all four mutations were found in patients with bilateral tumors. It therefore appears that bilaterality is a prominent phenotypic halmark of BRCA1 p … More redisposition. These results provide informations for understanding the role of BRCA1 gene mutation in familial forms of breast tumors and will contribute to genetic counseling and presymtomatic diagnosis of members in breast cancer families.To better understand the frequency, distribution and nature of BRCA1 mutations Japanese breast cancer patients, we screened 1,000 unselected primary cancers f mutations in exon 11, which accounts for 61% of the entire BRCA1 coding sequence. Using method based on multiplex single-strand conformational polymorphism (SSCP) analysis multiple restriction fragments generated by restriction-enzyme digestion of amplified DNA,w identified eight mutations including four that we had previously found in a subset of thes cases. All eight were germline mutations ; four of them were non-sense mutations or sma deletions resulting in premature stop codons, and the other four were missense mutation. The Japanese carriers of these mutant BRCA1 alleles had developed breast cancers at age ranging from 45 to 62, five of them bilaterally. Taking into account the effect of various facto such as life-time risk of breast cancer, screening efficiency, and the region examined, w roughly estimate that 2-3 % of breast cancer in Japan is attributable to BRCA1 mutation ar that 1 in 1,500-2,000 Japanese women carry a germline mutation in the BRCA1 gene. Less

最近，我们在 17-9 个相关乳腺癌和卵巢癌家族中发现了 BRCA1 基因的易感突变，其中包括 46 例早发乳腺癌病例（年龄 <35 岁）、12 例家族聚集病例和 59 例双侧癌症。使用单链构象多态性 (SSCP) 分析在这组 103 名患者中检测到 BRCA1 基因的整个编码外显子的突变；由于密码子 797 处的 2-bp 缺失、密码子 1214 处的无义突变、两个错义突变，一个位于密码子 271 处导致 Val->Met 替换，另一个位于密码子 1150 处导致 Pro->Ser 替换而导致火焰转移。所有这些都是种系突变；在这些肿瘤中没有发现体细胞突变，这一发现支持 BRCA1 在乳腺癌发生中的作用相当有限。在双侧肿瘤患者中发现，因此，双侧性似乎是 BRCA1 p 再倾向的一个显着表型标志，这些结果为了解 BRCA1 基因突变在家族性乳腺肿瘤中的作用提供了信息，并将有助于遗传咨询和治疗。乳腺癌家族成员的症状前诊断。为了更好地了解日本乳腺癌患者 BRCA1 突变的频率、分布和性质，我们筛查了 1,000 名未选择的原发癌症 f 外显子突变11，占整个 BRCA1 编码序列的 61%，使用基于多重单链构象多态性 (SSCP) 分析的方法，通过限制性酶消化扩增的 DNA 产生多个限制性片段，鉴定出 8 个突变，其中包括我们的 4 个突变。之前在这些病例的一个子集中发现了所有八个都是种系突变；其中四个是无义突变或导致提前终止密码子的 sma 缺失，另外四个是错义突变。这些突变BRCA1等位基因携带者在45岁至62岁之间罹患乳腺癌，其中5例为双侧乳腺癌，考虑到终生患乳腺癌的风险、筛查效率和检查区域等各种因素的影响，w。粗略估计，日本 2-3% 的乳腺癌归因于 BRCA1 突变，每 1,500-2,000 名日本女性中就有 1 人携带 BRCA1 基因种系突变。