转移性结直肠癌配对样本错配修复状态的异质性研究

Heterogeneity of mismatch repair status in paired samples of metastatic colorectal cancer

目的探讨转移性结直肠癌(mCRC)原发灶及配对转移灶错配修复(MMR)状态的一致性。方法收集2016年1月至2020年1月在天津医科大学总医院普外科诊断为mCRC且可获得配对样本患者的临床病理信息,采用免疫组织化学方法检测4种MMR蛋白(MSH2、MSH6、MLH1、PMS2)表达,确定配对样本MMR状态,分析其与患者临床病理参数的关系;根据原发灶MMR状态分为错配修复缺陷(dMMR)组和错配修复完整(pMMR)组,根据配对样本MMR状态分为异质性组和非异质性组,组间比较采用t检验、Mann-Whitney U检验和χ^(2)检验。结果共纳入84例患者。84例原发灶样本中,9例[10.7%(9/84)]呈dMMR,75例[89.3%(75/84)]呈pMMR,dMMR组较pMMR组肿瘤更多位于右半结肠[88.9%(8/9)比42.7%(32/75),χ^(2)=7.168,P<0.05]、原发肿瘤直径更大(7.00 cm比4.00 cm,Z=2.555,P<0.01)、分化程度更差[66.7%(6/9)比21.3%(16/75),χ^(2)=8.543,P<0.01];84例配对样本中,2例[2.4%(2/84)]呈单个MMR蛋白差异表达,10例[11.9%(10/84)]呈MMR状态异质性,包括4例[4.8%(4/84)]原发灶dMMR、转移灶pMMR,6例[7.1%(6/84)]原发灶pMMR、转移灶dMMR,统计学分析显示,与非异质性组比较,异质性组具有较大原发肿瘤直径(5.75 cm比4.50 cm,Z=1.988,P<0.05)和较差分化程度[70.0%(7/10)比20.3%(15/74),χ^(2)=11.271,P<0.01]。结论10.7%的mCRC配对样本MMR状态表现出异质性,在制定治疗策略时应多点、多部位取样,综合考虑原发灶和转移灶的MMR状态。

Objective To investigate the consistency of mismatch repair(MMR)status between primary tumor and paired metastatic tumor of metastatic colorectal cancer(mCRC).Methods From January 2016 to January 2020,the clinicopathological information of paired samples from patients with mCRC in the General Surgery Department of Tianjin Medical University General Hospital was gathered retrospectively.The MMR status of paired samples was compared and the association between MMR status and clinicopathological features of patients was analyzed.The immunohistochemical methods were employed to detect the expression of four MMR proteins(MSH2,MSH6,MLH1,PMS2).According to the MMR status of primary tumor,the patients were divided into deficient mismatch repair(dMMR)group and proficient mismatch repair(pMMR)group.According to the MMR status of paired samples,the patients were divided into heterogeneous group and non-heterogeneous group.T test,Mann-Whitney U test andχ^(2) test were used for comparison between groups.Results A total of 84 patients were included.Ther were 9 cases of dMMR[10.7%(9/84)],and 75 cases of pMMR[89.3%(75/84)].The dMMR group was more prevalent in the right colon[88.9%(8/9)vs.42.7%(32/75),χ^(2)=7.168,P<0.05],had larger primary tumor diameter(7.00 cm vs.4.00 cm,Z=2.555,P<0.01),and poorer differentiated degree[66.7%(6/9)vs.21.3%(16/75),χ^(2)=8.543,P<0.01]than pMMR group.Of the 84 paired samples,2[2.4%(2/84)]showed differential expression of a single MMR protein,and 10[11.9%(10/84)]showed heterogeneity of MMR status,including 4 patients[4.8%(4/84)]with primary dMMR metastatic pMMR and 6 patients[7.1%(6/84)]with primary pMMR metastatic dMMR.Statistical analysis showed that the heterogeneous group had a larger primary tumor diameter(5.75 cm vs.4.50 cm,Z=1.988,P<0.05)and poorer degree of differentiation than the non-heterogeneous group[70.0%(7/10)vs.20.3%(15/74),χ^(2)=11.271,P<0.01].Conclusion 10.7%of mCRC paired samples had heterogeneous MMR status.The MMR status of primary and metastatic tumors should be evaluated completely in the creation of treatment options,as should multipoint and multisite sampling.