子宫内膜样腺癌和癌前病变组织错配修复蛋白表达分析

Expressions of mismatch repair proteins in endometrioid adenocarcinoma and precancerous lesions

目的研究子宫内膜样腺癌、非典型增生、复杂性增生和正常增生周期宫内膜中DNA错配修复基因(mismatch repair gene,MMR)MLH1、MSH2、PMS2和MSH6蛋白的表达情况,探讨微卫星不稳定性(MSI)与子宫内膜样腺癌和癌前病变的发生及临床病理特征的关系。方法选取新疆医科大学第一附属医院病理科2006-06-01-2013-03-01子宫内膜样腺癌101例、子宫内膜非典型增生50例、子宫内膜复杂性增生50例和2010-10-01-2013-10-01确诊为正常增生周期宫内膜50例作为对照。采用免疫组织化学检测DNA MMR蛋白在不同子宫内膜病变中的表达,应用SPSS 17.0统计学软件进行统计学分析。结果子宫内膜样腺癌组织MMR蛋白失表达率分别为MLH1 32.7%(33/101)、MSH228.7%(29/101)、PMS2 16.8%(17/101)和MSH6 8.9%(9/101),明显高于子宫内膜非典型增生组织MLH1 12.0%(6/50)、MSH2 14.0%(7/50)、PMS2 12.0%(6/50)和MSH6 8.0%(4/50),复杂性增生组织MLH1 2.0%(1/50)、MSH2 14.0%(7/50)、PMS2 8.0%(4/50)、MSH6 2.0%(1/50)及正常增生期宫内膜组织MSH2 2.0%(4/50),其中MLH1、MSH2和PMS2失表达在各组间的差异有统计学意义,P<0.05;MSH6失表达率在各组间差异无统计学意义,P=0.077。MMR中4种蛋白的表达与子宫内膜样腺癌患者年龄、族别、肿瘤分期和分化、淋巴结转移无关,但MSI-H表型更倾向于发生在肌层浸润≥1/2病例中,P=0.005。MSI-H、MSI-L和MSS在子宫内膜样腺癌、非典型增生、复杂性增生及正常增生期宫内膜组织中的表型差异有统计学意义,P<0.001。子宫内膜非典型增生组织中MSI表型在年龄≤50岁和>50岁之间差异有统计学意义,P=0.001。结论 MMR蛋白MLH1、MSH2、PMS2和MSH6的失表达可能是子宫内膜样腺癌的早期分子事件。在临床病理指标上,MSI-H表型仅与肿瘤肌层浸润≥1/2状态相关,与患者的年龄、族别、肿瘤的分期和分化程度及淋巴结转移无明显相关性。非典型增生组织中MSI-H多见于≤50岁患者,其发生可能促进子宫内膜癌前病变进展为癌。

OBJECTIVE To explore the expression of mismatch repair proteins（MLH1,MSH2,PMS2 and MSH6）,microsatellite instability（MSI）and its clinicalpathological significance in endometrioid adenocarcinoma,atypical endometrial hyperplasia,complex hyperplasia and endometrium proliferative.To analyze the relationship between microsatellite instability＇s and endometrioid adenocarcinoma,precancerous lesions.METHODS We selected 101 cases of endometrioid adenocarcinoma,50 cases of atypical endometrial hyperplasia,50 cases of complex endometrial hyperplasia from Department of Pathology,First Affiliated Hospital,Xinjiang Medical University from 2006-06-01 to 2013-03-01,then selected 50 cases of normal endometrium proliferative from 2010-10-01 to 2013-10-01 as control.Using EnVision method to detect the expression of DNA mismatch repair protein in different endometrial lesions（including 101 cases of endometrioid adenocarcinoma,50 cases of atypical endometrial hyperplasia,50 cases of complex endometrial hyperplasia,50 cases of normal endometrium proliferative）and analyzing the relationship between their MSI and clinical features.RESULTS The rates of negative expression of MLH1（32.7%）,MSH2（28.7%）,PMS2（16.8%）and MSH6（8.9%）were all the highest in endometrioid adenocarcinoma,while atypical endometrial hyperplasia,complex hyperplasia and normal proliferative endometrium trend to decrease in them.There were statistical significance in the rates of MLH1,MSH2,PMS2（P0.05）,while no statistical significance in the rate of MSH6（P=0.077）in the four groups.The expression of MMR protein had no relationship with clinicopathological parameters including age,races,tumorous staging,differentiation,lymph metastasis,although MSI-H group was more frequently seen in patients of muscular invasion≥1/2（P=0.005）.There were statistical significance in phenotypes of MSI-H＇s and MSI-L＇s in the four groups（P〈0.001）,while there were statistical significance in endometrioid adenocarcinoma atypical endometrial hyperplasia and endometrium proliferative,also in atypical endometrial hyperplasia and endometrium proliferative（P〈0.001）.The expression of MSI-H and MSI-L were higer in over-50 sin endometrial tissue（P=0.001）.CONCLUSION The negative expression of MMR proteins（MLH1,MSH2,PMS2 and MSH6）is an early molecular event in endometrioid adenocarcinoma.With the exception of the correlation of MSI-H group expression with higher muscular invasion≥1/2,the expression of MMR proteins in EEC has no significant relationship with clinicopathological parameters including age,the races,tumorous staging,differentiation,lymph metastasis.MSI-H is more commonly expressed in atypical endometrial hyperplasia especially more at 50years-old and may promote development of endometrial precancerous lesions.