The Expression And The Clinical Significance Of MGMT, HMLH1 In Human Gastric Carcinoma

Background:An accumulation of multiple alterations in oncogenes and tumor suppressorgenes and tumor suppressor genes participates in carcinogenesis and the progressionof gastric cancer. Gene abnormalities also differ in accordance with the histologic typeof this malignancy. However, the mechanism through which the multiple genemutations accumulate during carcinogenesis or tumor progression in gastric cancer isnot well understood. Alkylating mutagens that are either externally administered orproduced through endogenous metabolic pathways lead to chemical modifications ofcellular DNA. O~6-Methylguanine formed on DNA strands after exposure to alkylationsubstances appears to responsible for the induction of gene mutation. Subsequentgene mutations triggered by O~6-methylguanine on DNA strands may accumulate andresult in the development of cancer. MGMT is a repair enzyme that protects againstalkylating carcinogens such as methylnitrosourea (MNU). MGMT transfers a methylgroup from O~6-methylguanine produced by MNU, to a cystein residue of the MGMTmolecule itself, Thus MGMT protects against gene mutation caused by alkylatingagents, and a loss of MGMT expression is thought to bring about gene mutation andlead to the development of cancer. On the other hand, MGMT levels in cancer cellsoften correlate to their sensitivity to chemotherapeutic agents. The increased quantityof MGMT generally correlates with the tumor's decreased response to alkylatingagentsThe mismatch repair (MMR) system is required for the cell to accurately copy its genome during cellular proliferation. Defieciencies of this system result in mutationrates 100-fold greater than those observed in normal cells. These mutations areparticularly evident at microsatellite sequences, consisting of repeats of 1-4 bp.Microsatellite instability (MSI) is thereby a hallmark of MMR gene-deficient cancers.Especially, hereditary nonpolyposis colorectal cancer (HNPCC) is associated withgermline mutations in two MMR genes, hMLH 1 and hMSH2.Cells with a competent MMR system would attempt to repair theO~6-methylguanine-thymine lesion, but without MGMT present, would become caughtin a vicious futile cycle leading to chromosome alterations, such as double strandbreaks and cytotoxicity. Given the relationship of MGMT/hMLH1 and their activityto O~6-meG repair, MGMT/hMLH1 activity might be an important prognosticator for achemotherapeutic regimens' success, particularly with those selectivechemotherapeutic agents that cause O~6-meG adducts and/or cross links.Objective:To investigate the expression and correlation of MGMT(O~6-methylguanine-DNA methyltransferase) and mismatch repair (MMR) systemprotein hMLH1 in gastric carcinoma tissues, at the same time, to investigate therelationship between their expression and the clinicopathological features of gastriccarcinoma studied. This study was aimed to explore the role of the two DNA repairenzymes, MGMT and hMLH1, in the carcinogenesis,progression and prognosis ofgastric carcinoma, and relationship of biological behaviors of gastric carcinoma andgene-expression. Methods:We investigated the expression of the DNA repair enzyme that protects againstalkylating mutagens, O~6-methylguanine DNA methyltransferase (MGMT), and themismatch repair (MMR) enzyme hMLH1 in 142 gastric cancer specimens and therelating normal tissue specimens adjacent to the tumor (＜6cm) byimmunohistochemical means. The relationship between clinicopathologic features andexpression of MGMT and hMLH1 proteins were studied.Results:The positive rates of MGMT and hMLH1 in the gastric carcinomas and normaladjacent tissue were 59. 86% (85/142),52.11% (74/142) and 90.85% (129/142),92.96% (132/142), respectively. And there are statistically significances in theexpression levels of MGMT and hMLH1 between the gastric carcinomas and theadjacent normal gastric mucous tissue (P＜0.05). The differences of the expressions ofMGMT and hMLH1 is statistically significant in Lauren's classification, tumorinfiltration, lymph node metastasizing, tumor stage and recurrence/metastasis after theoperation(P＜0.05), whereas there were no differences in age and gender(P＞0.05). Thegeneral rate of two- and five-year survival time after the radical gastrectomy were78% and 54%, respectively. Although there were no statistical significance in thetwo-year survival time rate (84% vs 54%) and five-year survival time rate (58% vs64%), the chemotherapeutic group after the operation was better than thenon-chemotherapeutic group. In the group of adjuvant chemotherapy, the two-yearand five-year survival time rate of MGMT(-) and MGMT(+) were 90%, 66% and 70%, 52%, respectively, and the differences between the subgroup of MGMT(-) andMGMT(+) were significant(P＜0.05); the two-year and five-year survival time rateof hMLH1(+) and hMLH1(-) were 88%, 63% and 72%, 53%, respectively, and thedifferences between the subgroup of hMLH1(+) and hMLH1(-) weresignificant(P＜0.05). In the group of non-chemotherapy, the two-year and five-yearsurvival time rate of MGMT(+) and MGMT(-) were 80%, 52% and 64%, 37%,respectively, and the differences between the subgroup of MGMT(+) and MGMT(-)were significant(P＜0.05); the two-year and five-year survival rate of hMLH1(+) andhMLH1(-) were 81%, 52% and 60%, 34%, respectively, and the differences betweenthe subgroup of hMLH1(+) and hMLH1(-) were significant(P＜0.05).Conclusions:1. The expressions of MGMT and hMLH1 proteins were reduced in gastriccarcinomas comparing to that of the adjacent normal gastric mucous tissue, and thedifferences were significant (P＜0.05), suggesting that the reduced expressions ofMGMT and hMLH1 may play a role in the carcinogenesis or early stage of the gastriccarcinoma.2. In the Lauren's classification, the positive rates of MGMT and hMLH1 in theintestinal type were higher than that in the diffused type; and the expressions ofMGMT and hMLH1 were also reduced in the deeper infiltration, more positive lymphnodes and advanced stage tumors. The differences of above findings were significant(P＜0.05), suggesting that the reduced expressions of MGMT and hMLH1 play a rolein the progression from early to advanced stage.3. The survival curve in 142 patients showed that, although the difference was notsignificant, both the two-year and five-year survival rate of the adjuvantchemotherapeutic group were higher than that of the non-chemotherapeutic group,indicating that adjuvant chemotherapy play a role for the benefit of the patient after the operation. In adjuvant chemotherapy group, the prognosis of the MGMT(-)/hMLH1(+) subgroup was better than that of the MGMT(+)/hMLH1(-)subgroup(P＜0.05), suggesting that rumors with a positive expression of MGMT havea property of chemotherapeutic resistance, while the protein hMLH1 may enhance thecytotoxicity of the chemotherapeutic drugs, such as cyclophosphamide, ifosfamide,cisplatin, carboplatin and oxaliplatin, et al. In non-adjuvant chemotherapy group, theprognosis of the MGMT(+)/hMLH1(+) subgroup was better than that of theMGMT(-)/hMLH1(-) subgroup (P＜0.05), suggesting that both the proteins ofMGMT and hMLH1 have the potential of inhibiting or delaying the progression of thegastric cancer cells.