错配修复缺陷型子宫内膜样癌分子亚组的临床病理特征及高频突变基因分析

Clinicopathological features of different molecular subtypes and high frequency mutations in endometrial endometrioid carcinoma with mismatch repair deficiency

目的了解错配修复缺陷型子宫内膜样癌(dMMR EEC)中不同分子机制亚组的临床病理特征及常见基因突变特征。方法收集54例dMMR EEC的临床病理信息,进行NGS检测及甲基化特异性PCR检测。根据MMR基因胚系突变及MLH1启动子甲基化检测结果分为:林奇综合征组、MLH1启动子高甲基化组、林奇样组。分析3个分子亚组间临床病理特征、预后及基因突变频率的差异,并探讨dMMR EEC中常见基因突变谱特征。结果在54例dMMR EEC中,林奇综合征组患者的平均和中位确诊年龄均明显小于MLH1启动子高甲基化组和林奇样组(P<0.05)。dMMR EEC中突变频率最高的10个基因依次为PTEN(90.7%)、PIK3CA(61.1%)、RNF43(35.2%)、FAT1(22.2%)、FAT2(22.2%)、RAD50(22.2%)、KRAS(20.4%)、CTNNB1(20.4%)、TP53(20.4%)、ATM(20.4%),其中PTEN与PIK3CA基因联合突变率为59%。结论除林奇综合征组确诊年龄较早外,dMMR EEC各分子亚组间具有相似的临床病理特征与预后。dMMR EEC具有独特的基因突变特征,PI3K-AKT信号通路分子改变在其发生发展过程中发挥重要作用;同源重组修复基因突变频率较高,有望提供更多的治疗选择。

Objective To understand the clinicopathological features of different molecular subtypes and common gene mutation characteristics in deficient mismatch repair(dMMR) endometrial endometrioid carcinoma(EEC). Methods Information about clinicopathological features of 54 dMMR EEC cases were collected. Targeted sequencing and MLH1 promoter hypermethylation analysis were performed. According to the result, the 54 samples were divided into Lynch syndrome(LS) group, MLH1-hypermethylated group, and Lynch-like syndrome(LLS) group. The differences in clinicopathological features, prognosis and frequency of common tumor driver gene mutations among 3 groups were analyzed, and characteristics of high frequency gene mutations in dMMR EEC were displayed. Results Among 54 cases of dMMR EEC, we found that patients in LS group were significantly younger than patients in MLH1-hypermethylated group and patients in LLS group(P<0.05). The top 10 most frequently mutated genes in dMMR EEC were PTEN(90.7%), PIK3 CA(61.1%), RNF43(35.2%), FAT1(22.2%), FAT2(22.2%), RAD50(22.2%), KRAS(20.4%), CTNNB1(20.4%), TP53(20.4%) and ATM(20.4%). Concurrent PTEN and PIK3 CA mutations were found in 59% of the patients. Conclusion Each molecular subgroup of dMMR EEC shows similar clinicopathological characteristics and prognosis, except for that patients in Lynch syndrome group is significantly younger. dMMR EEC displays characteristic gene mutation profile. Our findings suggest that PI3 K-AKT signaling pathway might play a key role in the pathogenesis of dMMR EEC. Additionally, the high mutation rate of homologous recombination repair(HRR) gene provides more options for dMMR EEC treatment.