Immunelogical diagnosis of MSI-positive gastrointestinal cancer and application for cancer vaccine

MSI阳性胃肠癌的免疫学诊断及癌症疫苗的应用

基本信息

批准号：
12470124
负责人：
IMAI Kohzoh
金额：
$ 8.13万
依托单位：
Sapporo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Microsatellite instability (MSI) due to defective DNA mismatch repair has been shown to play important roles in the development and progression of hereditary nonpolyposis colorectal cancer, a subset of sporadic cancers of the stomach, colorectum, and endometrium, and multiple primary cancers and multicentric cancers. Genetic alterations observed frequently in cancers with MSI are frameshift mutations in mononucleotide tracts present in coding regions of target genes. For example, deletion of one deoxyadenine in the stretch of 10 deoxyadenines in the TGF? Receptor type II gene results in a truncated protein that has 34 new amino acids on its carboxyl end. Many aberrant oligopeptides arise from frameshift mutations of target genes, such as the hMSH3, hMSH6, and BAX genes, in cancers with MSI. These aberrantoligopeptides are highly immunogenic and would be considered by the immune system as a nonself and could induce strong immune response.In support of this hypothesis, we have shown that frameshift mutations of the 2-microblobulin gene are frequently observed in gastric cancers with MSI and that these mutations are associated with unfavorable prognosis. These results suggest that cancers with frameshift mutations of the 2-micro globulin gene are under positive selective pressure for obliterating antigen presentation. Using immunoassay, we were able to detect antibodies directed against aberrant oligopeptides that were generated by frameshift mutations of the target genes in sera of MSI positive gastrointestinal cancer patients. We are also investigating T cell reactions.

由于DNA不匹配维修缺陷而导致的微卫星不稳定性（MSI）已显示出在遗传性非型非型物结直肠癌的发展和进展中起重要作用，胃，结直肠和子宫内膜的零星癌以及多种主要的癌症和多种癌症和多种癌症的一部分。在MSI癌症中经常观察到的遗传改变是靶基因编码区域中存在的单核苷酸区域中的移码突变。例如，在TGF中删除一种脱氧腺嘌呤在10种脱氧腺苷中的缺失？受体II型基因会导致一种截短的蛋白质，其羧基端具有34个新氨基酸。许多异常寡肽源是靶基因的移码突变，例如HMSH3，HMSH6和BAX基因，在患有MSI的癌症中。这些尺寸的异抗肽具有高度免疫原性，免疫系统将视为非自然的，并可能引起强烈的免疫反应。在支持这一假设的情况下，我们表明，在具有MSI的胃癌中，经常观察到2-霉菌蛋白基因的自降突变，这些突变与这些突变有关，这些突变与这些突变有关。这些结果表明，具有2-微球蛋白基因的移码突变的癌症在抑制抗原表现的阳性选择压力下。使用免疫测定，我们能够检测针对异常寡肽的抗体，这些抗体是由MSI阳性胃肠道癌患者血清中靶基因移封突变产生的。我们还正在研究T细胞反应。