The Protein Expression, Mutation And Methylation Of Mismatch Repair Gene HMSH2 And HMLH1 In Gastrointestinal Cancer

Background & Objective:Gastrointestinal cancer, especially gastric and colorectal cancers, is most common one in our country. Many factors and genes are related to their carcinogenesis, but the exact mechanism is clear. In order to maintain the stability of heredity and the accuracy of DNA replication, there is an integrated DNA repair system, which can repair DNA damage or mutation in either bacteria or human. The system is called mismatch repair system whose function is to repair the mismatch of nucleotide in replication and avoid the accumulation of replication errors. The main genes of this system are called mismatch repair genes (MMR). In MMR, hMSH2 gene as the relative gene for hereditary non-polyposis colorectal cancer (HNPCC) was first confirmed in 1993. After that, homological genes of MutS being hMSH3 and hMSH6; homological genes of MutL being hMLH1, hMLH3, hPMS1 and hPMS2 are confirmed in succession. Function deficiency of hMSH2 and hMLHl gene has been observed in 60% and 30% HNPCC patents, respectively. This deficiency results in the accumulation of mutation and genome instability, induces the growth of cells out of control, and finally cancer occurs. In following studies, deficiency of MMR was approved not only related to carcinogenesis of hereditary carcinoma as HNPCC but also sporadic carcinoma, especially gastrointestinal cancer.What role the MMR plays in carcinogenesis as well as development of gastrointestinal cancer is noticeable. This study is designed to discuss this question by analyzing the protein expression, mutation and methylation of MMR in sporadic gastric cancer and colorectal cancer.Materials and Methods:Gastric endoscopic biopsy specimens of 76 stomach cancer with their surrounding mucosa were got from the first affiliated hospital of Dalian medical university from 2002-2003. Helicobactor pylori (Hp) infection was detected by Quick-ureolytase method; Immunohistochemistry staining was used to exam the protein expressions of hMSH2 and hMLH1 in tumor tissues and their surrounding mucosa. Operation specimens of 45 colorectal cancers were got from the second affiliated hospital of Dalian medical university from 2001-2002. Immunoblotting was used to exam the protein expressions of hMSH2 and hMLH1; the mutations of hMSH2 in exon 5,7,12 and the mutations of hMLHl in exon 3,8,13 and 16 were determined by CE-PCR-SSCP-DNA sequence; restriction endonucleases-PCR was used to detect the methylation of hMLHl.chi-square, t test and oneway analysis of variance were used for statistic analysis.Results:1. The protein expressions of hMSH2 and hMLHl in stomach cancers and its correlation to Hp infection1) The positive rate (67.1%) of hMSH2 expression in cancer tissue was significantly higher than that in surrounding mucosa (35.5%) (P0.05); the positive rate(81.1%) of hMSH2 expression in poor differentiation carcinoma group was significantly higher than those in well and middle one (54.5%) and mucoid carcinoma group (54.5%) (PO.05), but there was no significant difference between the latter two groups(P>0.05).2) There was no significant difference between the positive rate of hMLHl expression in cancer tissue (81.6%) and that in surrounding mucosa (90.8%)(P>0.05). The positive rate (47.1%) of hMLHl expressionin mucoid carcinoma group was significantly lower than that in well middle differentiation group (81.8%) or poor differentiation group 97.3%(P<0.05), but there was no significant difference between the latter two groups (P>0.05).3) In cancer tissue, the positive rate (56.8%) of hMSH2 expression in Hp infection group was significantly lower than that in the group without infection (81.3%) (P0.05); the positive rate of hMLH1 expression was 77.2% in Hp infection group and 87.5% in the group without infection, but there was no significant difference between two groups (P>0.05). In surrounding mucosa, the positive rate of hMSH2 expression was 29.5% in Hp infection group and 43.8% in the group without infection, as well as those of hMLHl were 86.4% and 96.9%, there were no signific...