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Analysis of tumor suppressor genes for breast cancer

乳腺癌抑癌基因分析

基本信息

批准号：
10151252
负责人：
MIKI Yoshio
金额：
$ 15.36万
依托单位：
Japanese Foundation For Cancer Research
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas (A)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至无数据
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10151252/
关键词：
Hereditary breast cancer BRCA1 BRCA2 Rad51 BRAP1 Two-hybrid method 遺伝子乳癌癌抑制遺伝子

项目摘要

Mutations in the BRCA1 and BRCA2 genes are involved in approximately 60% of familial breast cancers and these results indicate the existence of the 3rd major gene responsible for hereditary breast cancers. The isolation of this gene is important for the genetic testing of hereditary breast cancer. The yeast two-hybrid system was used to isolate BRCA2-binding proteins. We showed that BRCA2 formed a complex with Rad51 and the pattern of northern blot analysis of the Rad51 genewas closely similar to that of the BRCA2 gene. It is therefore possible that alterations of the Rad51 gene may be involved in the development of hereditary breast cancers. To investigate this possibility, we screened Japanese patients with hereditary breast cancer for Rad51 mutations and found a single alteration in exon 6. This was determined to be present in the germline in two patients with bilateral breast cancer. In both patients, blood DNAs showed G-to-A transition of the second nucleotide of codon 150, which … More results in the substitution of glutamine for arginine. Since this alteration was not present in patients with breast or colon cancer examined, we assume that this missense alteration is likely to represent a disease-associated mutation. Another candidate of BRCA2-binding protein, designated BRAP1, is highly homologous to Amphiphysin and BIN1, that were reported to be associated with breast carcinogenesis. The exon-intron boundaries of this gene were determined, and screening for germline mutation in breast cancer families and for somatic mutation in primary breast cancers was performed. Although no mutation was found in families and primary cancers, the expression level of the BRAP1 gene was detected to be remarkably decreased in breast cancer cell lines and pancreas cancer cell lines.We have described the possibility that a small portion of bilateral breast cancers is due to germline alterations of Rad51. However, the 3rd major breast cancer susceptibility gene remains unknown ; intense efforts will be required to isolate the gene (s) responsible. Less

大约60%的家族性乳腺癌与BRCA1和BRCA2基因突变有关，这些结果表明存在导致遗传性乳腺癌的第三个主要基因。该基因的分离对遗传性乳腺癌的基因检测具有重要意义。利用酵母双杂交系统分离brca2结合蛋白。我们发现BRCA2与Rad51形成复合体，Rad51基因的northern blot分析模式与BRCA2基因的模式非常相似。因此，Rad51基因的改变可能与遗传性乳腺癌的发生有关。为了研究这种可能性，我们筛选了日本遗传性乳腺癌患者的Rad51突变，并在第6外显子发现了一个单一的改变。这在两名双侧乳腺癌患者的生殖系中被证实存在。在这两例患者的血液dna中，密码子150的第二个核苷酸显示G-to-A转变，这导致谷氨酰胺取代精氨酸。由于这种改变在乳腺癌或结肠癌患者中不存在，我们假设这种错义改变可能代表一种与疾病相关的突变。另一种候选brca2结合蛋白BRAP1与Amphiphysin和BIN1高度同源，据报道，这两种蛋白与乳腺癌的发生有关。确定了该基因的外显子-内含子边界，并对乳腺癌家族的种系突变和原发性乳腺癌的体细胞突变进行了筛查。虽然在家族和原发癌症中未发现突变，但BRAP1基因在乳腺癌细胞系和胰腺癌细胞系中表达水平显著降低。我们已经描述了一小部分双侧乳腺癌是由Rad51的种系改变引起的可能性。然而，第三个主要的乳腺癌易感基因仍然未知；需要付出巨大的努力才能分离出致病基因。少