| Research Abstract |
DNA mismatch repair (MMR) genes are responsible to hereditary nonpolyposis colorectal cancer and some of sporadic colorectal cancers. MMR-deficient tumor cells exhibit a low level of resistance to some anti-cancer agents, such as cisplatin, adriamycin, and alkylating agents. To know the MMR status or microsatellite instability (MSI) status of tumor cells is critical for choosing a therapeutical protocol. In this study, we established methods for microdetection of hMSH2 and hMLH1 proteins with monoclonal antibodies and MSI status determination. Further, clinicopathologic features of 99 cases of sporadic colorectal cancer was investigated.
(1)MSI status
We selected 16 microsatellite markers and determined an efficient detection procedure for MSI status by studying in 90 cases of sporadic colorectal cancer.
(2)Expression of mismatch repair proteins, hMSH2 and hMLH1
Expression of hMSH2 and hMLH1 proteins in 99 samples of sporadic colorectal cancer selected randomly was analyzes by Western blot
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and immunohistochemical staining with monoclonal antibodies developed in our laboratory. Totally 10 tumor samples with no/little expressing hMSH2 (4 samples) and hMLH1(6 samples) proteins were found, indicating approximately 10% of sporadic cases and 67% of the MSI tumor have some defects in the expression of these MMR proteins.
(3)Mutations in hMSH2 and hMLH1 genes
To know the molecular mechanism of the suppression of the gene expression, mutation in the exons were studied. Two kinds of mutations, which affect protein function, in a hMSH2-deficient sporadic case and one non-sense mutation in hMSH2-deficient a familial case were found. No mutation was found in hMLH1-deficient cases.
(4)Clinicopathologic features
Clinicopathologic features of 17 cases of MSI tumor showed similar characteristics to those frequently found in HNPCC cases such as right-sided location of the primary tumor, a lower frequency of well-differentiated adenocarcinoma, and Duke's staging A or B.
Further study is required to clarify the molecular mechanism of suppression of MMR gene expression, especially hMLH1 gene. In addition, since MMR-deficient or MSI tumors show a low level of drug-resistance, the specified protocol for treatment of MSI tumor should be developed. Less
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