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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错配修复缺陷引起的微卫星不稳定性（MSI）在遗传性非息肉病性结直肠癌、散发性胃癌、结直肠癌和子宫内膜癌以及多原发癌和多中心癌的发生和发展中起重要作用。在具有MSI的癌症中经常观察到的遗传改变是靶基因编码区中存在的单核苷酸片段中的移码突变。例如，在TGF？受体II型基因导致在其羧基末端具有34个新氨基酸的截短蛋白质。许多异常寡肽产生于MSI癌症中靶基因的移码突变，如hMSH 3、hMSH 6和BAX基因。这些异常肽具有高度的免疫原性，被免疫系统认为是非自身的，可以诱导强烈的免疫应答，为了支持这一假设，我们已经表明，移码突变的2-微球蛋白基因是经常观察到胃癌MSI和这些突变与预后不良。这些结果表明，2-微球蛋白基因移码突变的癌症是在积极的选择压力下消除抗原呈递。使用免疫测定，我们能够检测针对异常寡肽的抗体，所述异常寡肽由MSI阳性胃肠道癌患者血清中的靶基因的移码突变产生。我们也在研究T细胞反应。