不同错配修复状态结直肠癌患者临床病理特征及与KRAS/NRAS/BRAF基因突变的相关性

Clinicopathological Characteristics of Colorectal Cancer Patients with Different Mismatch Repair Statuses and Their Correlation with KRAS/NRAS/BRAF Gene Mutations

目的 探究不同错配修复(MMR)状态下结直肠癌患者的临床病理特征及与KRAS/NRAF/BRAF(KNB)基因突变的相关性。方法 收集477例结直肠癌患者临床病理资料,采用免疫组织化学染色(IHC)、PCR-毛细管电泳法、二代测序技术(NGS)分别检测MMR、微卫星不稳定性(MSI)及KNB状态,分析不同MMR状态分组下患者临床病理特征及与KNB突变的相关性。结果 与pMMR组相比,经典dMMR组患者年龄小、女性多、右半结肠常见、多为黏液腺癌且分化差(均P<0.05);非经典dMMR组患者右半结肠常见,且易见特殊组织学类型(均P<0.05)。经典/非经典dMMR组患者均常见MLH1-PMS2共缺失、BRAF突变和KRAS G13密码子突变(均P<0.05),且MMR IHC与MSI PCR结果高度一致(分别为100%和99.1%)。经典dMMR组KRAS突变的患者年龄小、男性多、易见特殊组织学类型,但远处转移少见(均P<0.05),而非经典dMMR组KRAS突变的患者淋巴结转移少见(P=0.005)。非经典dMMR组患者中MSH6基因突变率较高(P=0.002),均为MLH1-PMS2完全缺失合并MSH6非经典表达(100%)。5例含髓样癌成分的患者均存在MLH1-PMS2完全缺失,其中3例合并MSH2/MSH6非经典表达,这3例中有2例携带MSH6基因c.3261位点突变。结论 经典/非经典dMMR结直肠癌患者具有不同于pMMR患者的临床病理特征,MMR IHC检测可很好预测MSI状态。KRAS突变的经典/非经典dMMR结直肠癌患者之间临床病理特征不同,但均常见MLH1-PMS2共缺失、BRAF突变和KRAS G13密码子突变。非经典dMMR患者常见MLH1-PMS2完全缺失合并MSH6非经典表达模式。MSH6基因突变可在部分含髓样癌成分的结直肠癌发生中起关键作用。

Objective To investigate the clinicopathological characteristics of colorectal cancer patients with different mismatch repair(MMR)statuses and their correlation with KRAS/NRAF/BRAF(KNB)gene mutations.Methods The clinicopathological data of 477 patients with colorectal cancer were collected,and MMR,microsatellite instability(MSI),and KNB status were detected via immunohistochemistry(IHC),PCR–capillary electrophoresis,and next-generation sequencing(NGS),respectively.The clinicopathological features of patients with different MMR statuses and correlations with KNB mutations were analyzed.Results Compared with the patients in the pMMR group,the patients in the classical dMMR group were younger,included more females,and exhibited more tumors in the right colon,mostly mucinous adenocarcinoma and poorly differentiated tumors(all P<0.05).The tumors in the nonclassical dMMR group were commonly found in the right colon and were prone to special histologic types(all P<0.05).MLH1-PMS2 codeletion,BRAF mutation,and KRAS G13 codon mutation were common in patients in both the classical and the nonclassical dMMR groups(both P<0.05).The results of MMR IHC(100%)were highly consistent with those of MSI PCR(99.1%).Patients in the classical dMMR group with KRAS mutations were younger,included more males,and were prone to specific histologic types,but distant metastasis was rare(all P<0.05).Conversely,lymph node metastasis was rare in patients in the nonclassical dMMR group with KRAS mutations(P=0.005).The mutation rate of the MSH6 gene was relatively high in the nonclassical dMMR group(P=0.002),and all patients presented complete deletion of MLH1-PMS2 combined with nonclassical expression of MSH6(100%).Five patients with medullary carcinoma components had comp-lete deletions of MLH1-PMS2.Among the five patients,three had combined nonclassical expression of MSH2/MSH6.Two of the three patients carried the MSH6 gene c.3261 locus mutation.Conclusion The clinicopathologic features of patients with classical/nonclassical dMMR colorectal cancer differ from those of patients with pMMR,and MMR IHC could be used to predict effectively the MSI status.The clinicopathologic features differ between classical and nonclassical dMMR colorectal cancer patients with KRAS mutations,but both groups present codeletion of MLH1-PMS2,BRAF mutation,and KRAS G13 codon mutation.In patients with nonclassical dMMR,complete deletion of MLH1-PMS2 combined with nonclassical expression of MSH6 is common.Mutations in the MSH6 gene may play a key role in the development of colorectal cancer with medullary carcinoma components.