微卫星不稳定和RAS基因突变与Ⅲ~Ⅳ期大肠癌预后的相关性

Relationship between microsatellite instability, RAS gene mutation and prognosis of stage Ⅲ–Ⅳ colorectal cancer

目的:探讨Ⅲ~Ⅳ期大肠癌患者微卫星不稳定性(microsatellite instability,MSI)状态和RAS基因突变与临床病理特征及预后的关系。方法:检测202例Ⅲ~Ⅳ期大肠癌组织中KRAS,NRAS和B R A F基因突变情况以及MSI状态,分析不同临床病理参数组别的基因突变情况与预后的关系。结果:202例Ⅲ~Ⅳ期结直肠癌(colorectalcancer,CRC)中KRAS基因突变,BRAF突变和高度微卫星不稳定性(microsatellite instability-high,MSI-H)肿瘤主要发生在右半结肠,伴有黏液腺癌的肿瘤中,而p53突变更多发生在直肠,不伴有黏液腺癌的肿瘤中。单因素分析显示Ⅲ期CRC中,R AS突变型与野生型相比,无进展生存时间(progression-freesur v ivaltime,PFS)显著缩短(HR:1.804, 9 5%CI:1.159~2.808;P=0.009),在Ⅲ期CRC中,双野生型组(KRAS, NRAS, BRAF 3个基因中有1个突变的)与3个基因均是野生型的比较,PFS显著缩短(HR:1.962,95%CI:1.254~3.071;P=0.003)。同样,在多因素分析时,Ⅲ期CRC中RAS和BR A F均为野生型的患者,P FS与带有任一突变型的相比显著延长(H R:1.962, 95%CI:1.253~3.071;P=0.003)。而单因素、多因素分析,均未发现RAS突变、BRAF突变各亚组间总生存时间(overall survival time,OS)有统计学差异。结论:RAS,BRAF突变以及MSI状态对Ⅲ~Ⅳ期大肠癌预后有一定的预测作用,有待于大样本以及精细分组后的验证。

Objective: To investigate the relationship between RAS gene mutation, microsatellite instability(MSI) status and clinicopathological features and prognosis in patients with colorectal cancer. Methods: KRAS, NRAS and BRAF gene mutations and MSI status were examined in 202 patients with colorectal cancer. Statistical methods were used to analyze the relationship between gene mutations with clinicopathological features and prognosis in different groups, such as age, sex, tumor size, degree of differentiation, and so on. Results: KRAS gene mutation,BRAF gene mutation and microsatellite instability-high(MSI-H) tumor mainly occurred in the right colon with mucinous adenocarcinoma, while p53 mutation occurred more frequently in rectal tumors without mucinous adenocarcinoma. Univariate analysis showed that the progression-free survival time(PFS) of the RAS mutant in stage Ⅲ CRC was significantly shorter than that of the wild type(HR: 1.804, 95%CI: 1.159 to 2.808;P=0.009). In the stage Ⅲ CRC, the PFS of the double wild type group(one of the three genes KRAS, NRAS, BRAF) was significantly shorter than that of all three wild types(HR: 1.962, 95%CI: 1.254 to 3.071;P=0.003). Similarly, in multivariate analysis, both RAS and BRAF in stage Ⅲ CRC were wild type, PFS was significantly longer than that in patients with any mutant type(HR: 1.962, 95%CI: 1.253 to 3.071;P=0.003). However, univariate and multivariate analysis showed that there was no significant difference in overall survival(OS) time among RAS mutation and BRAF mutation subgroups. Conclusion: RAS, BRAF mutation and MSI status can predict the prognosis of stage Ⅲ and Ⅳ colorectal cancer, which need to be verified by large sample size and fine grouping.