错配修复蛋白在直肠癌中的表达及其对新辅助放化疗敏感性的预测价值

Expression of mismatch repair proteins in rectal cancer and its predictive value for sensitivity of neoadjuvant chemoradiotherapy

背景与目的:术前新辅助放化疗(nCRT)是治疗中低位局部进展期直肠癌的金标准,完全病理缓解(pCR)患者远期预后较好,尽管有新的分子生物学发展和诊疗技术进步,但对nCRT前可预测良好病理反应的潜在生物标志物甚少。本研究探讨错配修复(MMR)蛋白在局部进展期中低位直肠癌患者中表达情况,及其与nCRT敏感性的关系。方法:选取2014年1月—2019年12月在铜陵市人民医院胃肠外科住院治疗的162例中低位局部进展期直肠癌,所有患者均在nCRT后接受手术治疗。用免疫组化检测初诊肠镜活检组织标本中MMR蛋白(MLH1、MSH2、MSH6、PMS2)的表达,分析MMR蛋白表达状态与患者临床资料及nCRT疗效[按RECIST 1.1标准与肿瘤退缩分级(TRG)评分]的关系,以及患者TRG评分与临床病理因素及MMR蛋白表达状态的关系,并通过多因素Logistic回归模型分析pCR的影响因素。结果:162例直肠癌患者中22例(13.4%)存在MMR蛋白缺失(dMMR),其中MLH1蛋白缺失17例(10.5%)、MSH2蛋白缺失10例(6.2%)、MSH6蛋白缺失8例(4.9%)、PMS2蛋白缺失11例(6.8%)。组织学类型、术前临床分期、TRG评分与MMR蛋白表达状态有关(均P<0.05);dMMR患者RECIST 1.1评估nCRT的有效率高于MMR蛋白表达完整(pMMR)患者(59.1%vs.36.4%,P=0.043)。患者性别、年龄、肿瘤位置、分化程度、组织学类型、CEA水平、同步化疗方案以及MLH1、MSH2、MSH6、PMS2蛋白的表达与TRG评分无明显关系(均P>0.05);临床T分期、临床N分期、术前临床分期、MMR蛋白的表达状态(dMMR或pMMR)与TRG评分有关(均P<0.05)。Logistic多因素回归分析发现dMMR是患者pCR的独立影响因素(OR=0.327,95%CI=0.109~0.984,P=0.047)。结论:在局部进展期中低位直肠癌患者中,肠镜初诊活检组织中dMMR蛋白表型预示较好的nCRT疗效;MMR蛋白的表达状态可作为直肠癌患者nCRT疗效的预测指标。

Background and Aims:Neoadjuvant chemoradiotherapy(nCRT)is the gold standard for the treatment of mid-low locally advanced rectal cancer.Patients achieving pathologic complete remission(pCR)may have a better long-term prognosis.Despite the development of new molecular biology and progress of diagnosis and treatment technologies,there are few potential biomarkers for predicting good pathologic response before nCRT.This study was conducted to investigate the expression of mismatch repair(MMR)proteins in patients with mid-low locally advanced rectal cancer and their relationship with the sensitivity of nCRT.Methods:A total of 162 patients with mid-low locally advanced rectal cancer admitted in Gastrointestinal Surgery Department of Tongling People’s Hospital from January 2014 to December 2019 were enrolled.All patients underwent surgery following nCRT.The expressions of MMR proteins(MLH1,MSH2,MSH6 and PMS2)in their initial colonoscopic biopsy samples were detected by immunohistochemical staining.The relations of MMR protein expression status with clinical variables and nCRT efficacy[according to the RECIST 1.1 evaluation criteria and tumor regressive grading(TRG)score],as well as the relations of the TRG score with the clinicopathologic factors and MMR protein expression status were analyzed,and the influential factors for pCR were determined by multivariate Logistic regression model.Results:In the 162 patients,deficient MMR(dMMR)was found in 22 cases(13.4%),including MLH1 protein deletion in 17 cases(10.5%),MSH2 protein deletion in 10 cases(6.2%),MSH6 protein deletion in 8 cases(4.9%)and PMS2 protein deletion in 11 cases(6.8%).Histological type,preoperative clinical stage and TRG score were significantly associated with MMR protein expression status(all P<0.05).The effective rate assessed by RECIST 1.1 in dMMR patients was higher than that in patients with proficient MMR(pMMR)(59.1%vs.36.4%,P=0.043).The sex age,tumor location,differentiation,histological type,CEA level,synchronous chemotherapy regimen and expressions of MLH1,MSH2,MSH6 and PMS2 proteins were irrelevant to TRG score(all P>0.05),while the clinical T stage,clinical N stage,preoperative clinical stage,and the MMR protein expression status(dMMR or pMMR)were related to TRG score(all P<0.05).Logistic multivariate regression analysis revealed that dMMR was an independent influential factor for pCR of the patients(OR=0.327,95%CI=0.109–0.984,P=0.047).Conclusion:In patients with mid-low locally advanced rectal cancer,the dMMR protein phenotype presented in the tissue of initial colonoscopic biopsy indicates a better nCRT effect,and MMR protein expression status can be used as a predictor of nCRT efficacy for rectal cancer patients.