DNA错配修复蛋白表达与胃腺癌临床病理特征的关系及意义

目的:检测DNA错配修复（mismatch repair，MMR）主要蛋白（MLH1、MSH2、MSH6和PMS2)在人胃腺癌组织中的表达，并分析错配修复缺陷（defective mismatch repair，dMMR）与胃腺癌临床病理因素及预后的关系。方法:采用免疫组织化学染色法检测4种MMR蛋白（MLH1、MSH2、MSH6和PMS2)在120例人胃腺癌组织中的表达，并从癌症基因组图谱（The Cancer Genome Atlas，TCGA）公共数据库下载432例胃腺癌患者的临床病理资料和微卫星不稳定性（microsatellite instability，MSI）的检测结果，分析MSI与胃腺癌临床病理特征的关系，利用TCGA的数据分析高频度微卫星不稳定（MSI-H）与胃腺癌患者预后的关系。结果:免疫组化染色结果显示在120例胃腺癌组织中，MMR蛋白表达正常（pMMR）组106例（88.3%），MMR蛋白表达缺失（dMMR)组14例（11.7%），其中MLH1缺失2例（1.7%）、PMS2缺失13例（10.8%）、MLH1和PMS2共同缺失2例（1.7%）、MSH2和MSH6共同缺失1例（0.8%）。统计分析结果显示，dMMR与胃腺癌淋巴结转移相关（P=0.022），而与其他临床病理因素无关。TCGA数据统计分析结果显示，MSI-H与胃腺癌患者年龄（P=0.001)、性别（P=0.000)、原发肿瘤部位（P=0.000)、Lauren分型（P=0.011）、肿瘤浸润深度T分期（P=0.024)、淋巴结有无转移（P=0.008)有关。Kaplan-Meier生存分析结果显示MSI-H型胃腺癌患者有预后更好的趋势，但差异不具有统计学意义（P=0.070）。结论:120例中国胃腺癌患者中MSI/dMMR型胃腺癌占比为11.7%，且dMMR状态与胃腺癌的淋巴结转移呈负相关；MSI-H型胃腺癌患者具有年龄大、多为女性、肿瘤多位于胃远端、肿瘤浸润深度T分期低、无淋巴结转移的特征，且MSI-H型胃腺癌具有预后更好的趋势，但不具有统计学意义。MSI状态与胃癌预后的关系尚需进一步深入研究和大样本数据的验证。

Relationship between DNA mismatch repair protein expressions and clinicopathological features of stomach adenocarcinoma

Objective:To detect the expression pattern of MMR major proteins（MLH1，MSH2，MSH6 and PMS2) in stomach adenocarcinoma，and to analyze the relationship between mismatch repair defects（dMMR) and clinicopathological factors and prognosis of stomach adenocarcinoma.Methods:Immunohistochemistry was used to detect the expression of MMR major proteins in 120 stomach adenocarcinoma tissues，and the clinical pathological data and microsatellite instability status of 432 patients with stomach adenocarcinoma was downloaded from the Cancer Genome Atlas（TCGA) public database.The relationship between MSI and clinicopathological features of stomach adenocarcinoma was analyzed.The relationship between high frequency microsatellite instability（MSI-H) and prognosis of stomach adenocarcinoma from TCGA database was evaluated.Results:Of the 120 patients with stomach adenocarcinoma，106 cases（88.3%) had normal expression of MMR，14 cases（11.7%) had deletion of MMR，including 2 cases（1.7%) MLH1 deletion，13 cases（10.8%) PMS2 deletion，2 cases（1.7%) combined MLH1 and PMS2 deletion，and 1 case（0.8%) combined MSH2 and MSH6 deletion.Statistical analysis showed that dMMR was only associated with lymph node metastasis of stomach adenocarcinoma（P=0.022)，but was not related to other clinicopathological factors.Statistical analysis about 432 cases of stomach adenocarcinoma from TCGA database showed that MSI-H was significantly associated with age（P=0.001)，gender（P=0.000)，gastric cancer position（P=0.000)，Lauren type（P=0.011），T stage（P=0.024)，and lymph node metastasis（P=0.008).Kaplan-Meier analysis showed that the MSI-H stomach adenocarcinoma had a better prognosis，but there was no statistical difference（P=0.070).Conclusion:The proportion of MSI/dMMR in 120 stomach adenocarcinoma patients was 11.7%，and dMMR was negatively related to lymph node metastasis.MSI-H stomach adenocarcinoma patients have the characteristics of older age，more female，tumor located in the distal location of the stomach，lower T stage and non-lymph node metastasis.MSI-H stomach adenocarcinoma had a better prognosis，but there was no statistical difference.The relationships between MSI status and stomach adenocarcinoma prognosis need further research and validation from large sample data in future.