错配修复蛋白状态与不良临床病理特征对结肠癌患者预后的交互作用分析

Interaction analysis of mismatch repair protein and adverse clinicopathological features on prognosis of colon cancer

目的探讨错配修复蛋白状态与不良临床病理特征对Ⅰ~Ⅲ期结肠癌患者预后的交互效应。方法采用回顾性队列研究方法。收集2016年1月至2017年12月全国7家医院收治的1650例Ⅰ~Ⅲ期结肠癌患者的临床病理资料;男963例,女687例;年龄为62(53,71)岁。1650例患者根据错配修复蛋白状态分为错配修复蛋白表达缺失(dMMR)230例与错配修复蛋白表达完整(pMMR)1420例。观察指标:(1)不同错配修复蛋白状态患者的临床病理特征比较。(2)影响dMMR患者生存结局的因素分析。(3)影响pMMR患者生存结局的因素分析。(4)错配修复蛋白状态与不良临床病理特征对生存结局影响的交互作用分析。正态分布的计量资料以x±s表示,组间比较采用独立样本t检验;偏态分布的计量资料以M(Q_(1),Q_(3))表示,组间比较采用Mann-WhitneyU检验。计数资料以绝对数表示,组间比较采用χ^(2)检验或Fisher确切概率法。等级资料采用Mann-WhitneyU检验。缺失值使用随机森林插补法进行数据插补。单因素分析采用COX比例风险回归模型。多因素分析采用COX逐步回归(向前逐步回归法)。乘法交互效应的系数使用COX比例风险回归模型的交互项系数获得。加法交互效应使用交互作用超额相对危险度(RERI)进行评价。结果(1)不同错配修复蛋白状态患者的临床病理特征比较。dMMR和pMMR患者年龄、T分期、淋巴结检出数目、淋巴结检出数目<12枚、高级别肿瘤比较,差异均有统计学意义(P<0.05)。(2)影响dMMR患者生存结局的因素分析。多因素分析结果显示:T分期、N分期、淋巴结检出数目<12枚是影响dMMR患者无病生存的独立因素(风险比=3.548,2.589,6.702,95%可信区间为1.460~8.620,1.064~6.301,1.886~23.813,P<0.05);年龄、N分期是影响dMMR患者总生存的独立因素(风险比=1.073,10.684,95%可信区间为1.021~1.126,2.311~49.404,P<0.05)。(3)影响pMMR患者生存结局的因素分析。多因素分析结果显示:年龄、T分期、N分期、脉管瘤栓是影响pMMR患者无病生存的独立因素(风险比=1.018,2.214,2.598,1.549,95%可信区间为1.006~1.030,1.618~3.030,1.921~3.513,1.118~2.147,P<0.05);年龄、T分期、N分期、高级别肿瘤是影响pMMR患者总生存的独立因素(风险比=1.036,2.080,2.591,1.615,95%可信区间为1.020~1.052,1.407~3.075,1.791~3.748,1.114~2.341,P<0.05)。(4)错配修复蛋白状态与不良临床病理特征对生存结局影响的交互作用分析。交互作用结果显示:淋巴结检出数目<12枚与错配修复蛋白状态对结肠癌患者无病生存影响的乘法交互效应显著(风险比=3.923,95%可信区间为1.057~14.555,P<0.05);年龄、高级别肿瘤与错配修复蛋白状态对结肠癌患者总生存影响的加法交互效应显著(RERI=-0.033,-1.304,95%可信区间为-0.049~-0.018,-2.462~-0.146)。结论错配修复蛋白状态与不良临床病理特征(淋巴结检出数目<12枚、高级别肿瘤)在Ⅰ~Ⅲ期结肠癌患者的预后中存在交互作用。在dMMR患者中,淋巴结检查数目<12枚对预后不良的提示作用强;而在pMMR患者中,高级别肿瘤对预后不良的提示作用强。

Objective To investigate the interactive effect of mismatch repair(MMR)protein status and adverse clinicopathological features on prognosis of stageⅠ-Ⅲcolon cancer.Methods The retrospective cohort study was conducted.The clinicopathological data of 1650 patients with colon cancer of stageⅠ-Ⅲwho were admitted to 7 hospitals in China from January 2016 to December 2017 were collected.There were 963 males and 687 females,aged 62(53,71)years.Patients were classified as 230 cases of MMR deficiency(dMMR)and 1420 cases of MMR proficiency(pMMR)based on their MMR protein status.Observation indicators:(1)comparison of clinicopathological characteristics between patients of different MMR protein status;(2)analysis of factors affecting the survival outcomes of patients of dMMR;(3)analysis of factors affecting the survival outcomes of patients of pMMR;(4)interaction analysis of MMR and adverse clinicopathological features on survival outcomes.Measurement data with normal distribution were represented as Mean±SD,and comparison between groups was conducted using the independent t test.Measurement data with skewed distribution were represented as M(Q_(1),Q_(3)),and comparison between groups was conducted using the Mann-Whitney U test.Count data were described as absolute numbers,and comparison between groups was conducted using the chi-square test or Fisher exact probability.Comparison of ordinal data was conducted using the Mann-Whitney U test.The random forest interpolation method was used for missing values in data interpolation.Univariate analysis was conducted using the COX proportional risk regression model,and multivariate analysis was conducted using the COX stepwise regression with forward method.The coefficient of multiplication interaction effect was obtained using the interaction term coefficient of COX proportional risk regression model.Evaluation of additive interaction effects was conducted using the relative excess risk due to interaction(RERI).Results(1)Comparison of clinicopathological characteristics between patients of different MMR protein status.There were significant differences in age,T staging,the number of lymph node harvest,the number of lymph node harvest<12,high grade tumor between patients of dMMR and pMMR(P<0.05).(2)Analysis of factors affecting the survival outcomes of patients of dMMR.Results of multivariate analysis showed that T staging,N staging,the number of lymph node harvest<12 were independent factors affecting the disease-free survival(DFS)of colon cancer patients of dMMR(hazard ratio=3.548,2.589,6.702,95%confidence interval as 1.460-8.620,1.064-6.301,1.886-23.813,P<0.05).Age and N staging were independent factors affecting the overall survival(OS)of colon cancer patients of dMMR(hazard ratio=1.073,10.684,95%confidence interval as 1.021-1.126,2.311-49.404,P<0.05).(3)Analysis of factors affecting the survival outcomes of patients of pMMR.Results of multivariate analysis showed that age,T staging,N staging,vascular tumor thrombus were independent factors affecting the DFS of colon cancer patients of pMMR(hazard ratio=1.018,2.214,2.598,1.549,95%confidence interval as 1.006-1.030,1.618-3.030,1.921-3.513,1.118-2.147,P<0.05).Age,T staging,N staging,high grade tumor were independent factors affecting the OS of colon cancer patients of pMMR(hazard ratio=1.036,2.080,2.591,1.615,95%confidence interval as 1.020-1.052,1.407-3.075,1.791-3.748,1.114-2.341,P<0.05).(4)Interaction analysis of MMRand adverse clinicopathological features on survival outcomes.Results of interaction analysis showed that the multiplication interaction effect between the number of lymph node harvest<12 and MMR protein status was significant on DFS of colon cancer patients(hazard ratio=3.923,95%confidence interval as 1.057-14.555,P<0.05).The additive interaction effects between age and MMR protein status,between high grade tumor and MMR protein status were significant on OS of colon cancer patients(RERI=-0.033,-1.304,95%confidence interval as-0.049 to-0.018,-2.462 to-0.146).Conclusions There is an interaction between the MMR protein status and the adverse clinicopathological features(the number of lymph node harvest<12,high grade tumor)on prognosis of colon cancer patients of stageⅠ-Ⅲ.In patients of dMMR,the number of lymph node harvest<12 has a stronger predictive effect on poor prognosis.In patients of pMMR,the high grade tumor has a stronger predictive effect on poor prognosis.