Methylation Of The HMLH1 And HMSH2 Promoter Region In Endometrial Carcinoma

Objective:Methylation of the hMLHl promoter region is frequently observed in microsatellite instability (MSI)-positive sporadic endometrial carcinomas. The study was designed to explore associations between methylation of mismatch repair gene hMLHl, hMSH2 promoter and clinicopathological characteristics of hereditary and sporadic endometrial carcinomas and to detect aberrant methylation of hMLHl and hMSH2 in the peripheral blood lymphocyte of endometrial carcinoma or normal patients. It was also designed to study the role of CpG island methylation of hMLHl, hMSH2 in endometrial carcinoma tumorigenesis.Methods:We studied mismatch repair gene hMLHl and hMSH2 promoter methylation in 50 peripheral blood lymphocytes and 48 tumor tissues (13 hereditary endometrial carcinomas and 35 sporadic endometrial carcinomas) ,both endometrium and peripheral blood lymphocyte of 6 atypical hyperplasia and 34 healthy individuals (19 normal secretory endometriums and 15 normal proliferative endometriums).Methylation of the hMLHl promoter region was analyzed by methylation-sensitive restriction endonucleases polymerase chain reaction. Methylation of the hMSH2 promoter region was analyzed by methylation-specific polymerase chain reaction (MSP). The associations of hypermethylation of hMLHl and hMSH2 in tissues and blood of endometrial carcinoma patients with clinicopathological variables were then evaluated using chi-square test.Results:Methylation of the hMLHl and hMSH2 promoter region was found in 37.5% and 12.5% endometrial carcinoma respectively, whereas none of atypical hyperplasia and normal endometruim .Clinicopathological analysis revealed that hMLHl methylation in endometrial carcinomas tissue and blood was significantly associated with FIGO stage. There was no relationship between Methylation of the hMLHl promoter region and age, diabetes mellitus, hypertension, multiple primary cancers, cancer history, myometrial invasion, grades, lymphonode metastase. But There was no relationship between Methylation of hMSH2 promoter region and age, diabetes mellitus, hypertension, multiple primary cancers, cancer history, FIGO stage, myometrial invasion, grades, lymphonode metastase.37.5% (17/48) tumor tissue exhibited methylation of the hMLHl, among the 17 patients with methylation of the hMLHl, 8 (61.5%)methylation of the hMLHl was also detected in the lymphocyte of blood in 13 patient whose blood sample was obtained at the same time.Methylated sequences of hMSH2 promoter region can be detected in the blood of endometrial patients whose tumor tissue was proved to be methylated.There was no significant correlation between hereditary and sporadic endometrial carcinoma for methylation of both hMLHl and hMSH2.Conclusions:Methylation of hMLHl promoter in endometrial carcinoma was more than that in normal tissue.Methylation of hMLHl promoter in tumor tissue and peripheral blood of patient with endometrial carcinoma were significantly associated with FIGO stage .That is probably associated with early stage of endometrial cancer.Peripheral blood exhibited significant relationship with tumor tissue in...