The Correlations And Alterations Of HMLH1 Expression, PTEN Mutations And MSI In Endometrial Carcinoma

ObjectiveEndometrial carcinoma is the most common malignancy of women . Little is known about the molecular genetic events that contribute to its pathogenesis. En-dormetrial tumorigenesis through two divergent pathway: type I oestrogen - dependent;while type II oestrogen - independent. The most common genetic alterations of type I were microsatellite instability ( MSI) and PTEN mutations . The aim of the current study was to assess the prevalence and clinicopathologic significance of MSI ,expression of PTEN and hMLHl ,PTEN mutations and their correlations in endormetrial carcinogenesis.Methods1. We analyed the protein expressions of hMLHl and PTEN in 40cases of Uterine endometrial carcinoma (UEC) ,22cases of Atypical Hyperplasia of endo-metrium ( AH ) and 23 cases of Normal Endormetrium ( NE ) by immunohisto-chemistry S - P method . To evaluate the correlations between expressions of hMLH1, PTEN and analyze the alterations of expressions of hMLH1,PTEN in endormetrial carcinogenesis.2. The Microsatellite instability (MSI) analysis was performed using five microsatellite markers in paired UEC , AH. and study the correlation with expression of hMLH1. The levels of hMLHl protein inNE,AH,UECwere detected by Western - blot.3. PTEN mutations were detected by single - strand conformation polymorphism (PCR -SSCP) analysis and DNA sequencing in UEC,AHand NE. To de-termine whether PTEN mutations is relatived with MSI and its potential mechanism.Rescult1. The expressions of hMLHl and PTEN were degression which was statistical significance( p < 0.01);Interestingly, the expression of PTEN and PTEN mutations were changed significant in AH—the direct precursor to UEC ( p < 0. 01).2. The association between histological grade and hMLHl expression is significant (p <0.05)by immunohistochemitry or Western -blot;and PTEN mutations are significant with clinical stage of tumors( p <0.05) 0 It was no apparent correlation of MSI status with histologic type N degree of defferentiation^myome-trial invasion and lymph node invasion. PTEN mutations and MSI were detected only in endometrioid carcinoma.3. The association of the lack of staining for hMLHl protein with the MSI status in UEC is statistically significant ( p <0. 05) o PTEN has a substantially higher frequency of mutations in UEC with MSI compared with the frequency of mutations in UEC without MSI( p < 0.05 ).4. In UEC with MSI,PTEN mutations were detected in short coding mono-nucleotide repeats(A)5in 2 of 11 carcinomas(18.2% )5. To detect the expression of hMHl by immunohistochemistry S - P method and Western - blot has the similar rescults.Conclusions1. PTEN mutations and MSI are two of the most common genetic alterations in uterine endometrioid carcinoma 0 PTEN inactivation is a relatively early event in endometrial tumorigenesis, to detect the expression of PTEN by immunohistochemistry S - P method could be a new tool for diagnosis of early UEC, and expression of hMLHl could be a indicator of prognosis of UEC and a screening tool for patients froms AH to UEC.2. PTEN is a important target gene in endometiial carcinogenesis, and PTEN mutations may be secondary to deficiencies in mismatch repair and gives some explanation for the frequent presence of PTEN mutations in MSI positive UEC.