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

最近在17-9个相关的乳腺癌和卵巢癌家族中发现了BRCA1基因的易感突变。我们使用单链构象多态性（SSCP）分析了46例早期乳腺癌（<35岁）、12例家族性聚类和59例双侧乳腺癌（BRCA1基因全编码外显子突变）。在103例患者中检测到4个突变；密码子797缺失2个bp导致的火焰移位，密码子1214无义突变，两个错义突变，一个在密码子271导致Val->Met替换，另一个在密码子1150导致Pro->Ser替换。它们都是种系突变；在这些肿瘤中没有发现体细胞突变，这一发现支持了BRCA1在乳腺癌发生中的作用相当有限。在三个选择组中，所有四种突变都在双侧肿瘤患者中发现。因此，双侧性似乎是BRCA1基因显著的表型特征。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，并将有助于乳腺癌家族成员的遗传咨询和症状前诊断。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，我们筛选了1000例未选择的原发癌症11外显子突变，占整个BRCA1编码序列的61%。使用基于多重单链构象多态性（SSCP）的方法分析由扩增DNA的限制性内切酶酶切产生的多个限制性内切片段，我们确定了8个突变，其中4个是我们之前在这些病例的一个子集中发现的。所有8个都是种系突变；其中4个是非义突变或sma缺失导致过早终止密码子，另外4个是错义突变。携带这些突变BRCA1等位基因的日本人在45岁至62岁之间患上了乳腺癌，其中5人是双侧乳腺癌。考虑到各种因素的影响，如乳腺癌的终生风险、筛查效率和检查的地区，我们大致估计日本2- 3%的乳腺癌可归因于BRCA1突变，即每1,500-2,000名日本女性中就有1名携带BRCA1基因的种系突变。少

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