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

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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.