错配修复蛋白联合p53蛋白检测在肝细胞癌预后中的应用

Application of mismatch repair protein combined with p53 detection in prognosis of hepatocellular carcinoma

目的探讨错配修复(mismatch repair,MMR)蛋白和p53突变与肝细胞癌临床病理特征的关系及其在预后中的临床应用价值。方法收集220例肝细胞癌标本制作组织芯片,采用免疫组化EnVision两步法检测MMR蛋白(MLH1、MSH2、MSH6和PMS2)和p53蛋白的表达,并复习相关文献。结果肿瘤细胞MMR蛋白缺失率为64.9%(131/202),其与肿瘤大小、分化程度、转移部位相关(P=0.015、P=0.017、P=0.027);p53蛋白突变率为72.4%(152/210),其与分化程度、脉管内癌栓、AFP水平相关(P=0.009、P=0.019、P=0.003);单因素生存分析表明肿瘤大小、AFP水平、复发转移及部位是肝细胞癌预后较差的危险因素;Cox多因素回归模型表明肝细胞癌中肝外转移者死亡风险更高;MMR缺陷与p53突变无相关性;Kaplan-Meier生存分析显示单一MMR缺陷和p53与肝细胞癌患者的总生存期和无进展生存期无关,但MMR缺陷患者中p53与肝细胞癌患者总生存期(P=0.009)和无进展生存期(P=0.013)显著相关。结论肝细胞癌中有明显的MMR缺陷和p53突变,两者联合与肝细胞癌患者预后较差有关。

Purpose To investigate the relationship between mismatch repair(MMR)protein and p53 mutations and clinicopathological features of patients with hepatocellular carcinoma(HCC)and their clinical values in prognosis of HCC.Methods A total of 220 cases of HCC confirmed by pathology were collected.Tissue microarray was prepared and the expression of mismatch repair protein(MLH1,MSH2,MSH6 and PMS2)and p53 protein was detected by EnVision immunohistochemistry two-step method.And the relevant literature was reviewed.Results The rate of mismatch repair deletion in tumor cells was 64.9%(131/202),and associated with tumor size,degree of differentiation and metastasis site(P=0.015,P=0.017,P=0.027).p53 mutation rate was 72.4%(152/210)and associated with the degree of differentiation,intravascular tumor thrombus and AFP level(P=0.009,P=0.019,P=0.003).Single factor survival analysis showed that tumor size,AFP Level,recurrence and metastasis were risk factors for poor prognosis of HCC.Multi-factor Cox regression model showed that extrahepatic metastasis in patients with HCC had a higher risk of death.There was no relationship between mismatch repair deletion and p53 mutation.Kaplan-Meier analysis showed that although single mismatch repair deletion or p53 mutation was not associated with overall survival and progression-free survival,but in mismatch repair deletion patients p53 mutation was significantly related to overall survival(P=0.009)and progression-free survival(P=0.013)in HCC patients.Conclusion HCC cells showed obvious mismatch repair deletion and p53 mutation and combination of them was related to poor prognosis of HCC.