错配修复缺陷结直肠癌中NTRK基因融合变异的检测及其分子病理特征分析  

NTRK gene fusion and molecular pathological characteristics of mismatch repair deficient colorectal cancer

作　　者：康红 李杜娟 尤慧晗 向铮 成琼 孔令非 Kang Hong;Li Dujuan;You Huihan;Xiang Zheng;Cheng Qiong;Kong Lingfei(Department of Pathology,People′s Hospital of Zhengzhou University/People′s Hospital of Henan University,Zhengzhou 450043,China;Department of Pathology,Renmin Hospital of Wuhan University,Wuhan 430060,China)

机构地区：[1]河南省人民医院郑州大学人民医院河南大学人民医院病理科,郑州450043 [2]武汉大学人民医院病理科,武汉430060

出　　处：《中华病理学杂志》2025年第2期135-141,共7页Chinese Journal of Pathology

摘　　要：目的探讨pan-TRK免疫组织化学染色在错配修复缺陷(mismatch repair deficient,dMMR)结直肠癌NTRK基因融合变异检测中的价值,并分析伴有NTRK基因融合dMMR结直肠癌的分子病理特征。方法收集河南省人民医院病理科2020—2023年诊断为dMMR结直肠癌患者117例的组织蜡块,分别运用免疫组织化学、荧光原位杂交(FISH)、基于DNA/RNA二代测序检测肿瘤组织中pan-TRK蛋白表达情况及融合伴侣基因,进一步探讨pan-TRK染色模式与伴侣基因相关性。结果117例dMMR结直肠癌甲醛固定石蜡包埋样本均成功进行免疫组织化学和FISH检测。其中免疫组织化学pan-TRK阳性病例共15例(15/117,12.8%):6例肿瘤细胞膜及细胞质弥漫强阳性,2例肿瘤细胞质弥漫微弱颗粒状阳性,2例约5%肿瘤细胞核旁中等强度点状阳性,1例肿瘤细胞质及细胞膜弥漫中等至强颗粒状阳性,1例约60%肿瘤细胞质中等至弱颗粒状阳性,1例约1%的肿瘤细胞核强阳性,1例约3%肿瘤细胞核中等至强阳性,1例弥漫核旁中等强度点状阳性及核周弱颗粒状阳性。6例(6/117,5.1%)FISH检测出NTRK1基因断裂,该6例与pan-TRK弥漫强阳性表达病例一致。基于DNA/RNA二代测序进一步证实6例NTRK1基因断裂的病例均携带TPM3-NTRK1融合基因,同时均具有高频微卫星不稳定性及高肿瘤突变负荷,均未检测到KRAS、NRAS、BRAF V600E及TP53基因突变,4例携带环指蛋白43基因移码突变。其他分子改变包括:3例携带ROS1基因突变,2例同时携带BRAC、ALK、EGFR基因突变,2例携带ATM基因突变,2例携带KIT基因突变,均为无明确意义的错义/移码突变。免疫组织化学检测NTRK基因融合的灵敏度为100.0%,特异度为92.5%,膜/质弥漫强阳性的灵敏度及特异度均为100.0%。结论pan-TRK蛋白在dMMR结直肠癌中表达模式多样,弥漫强阳性表达高度提示NTRK1基因融合。TPM3-NTRK1基因融合是dMMR结直肠癌中较为常见的NTRK基因融合形式。Objective To investigate the expression pattern of pan-TRK protein in colorectal cancers with NTRK gene fusion and mismatch repair deficient(dMMR)and to analyze its molecular pathological characteristics.Methods A total of 117 dMMR colorectal cancers diagnosed in the Department of Pathology of Henan Provincial People′s Hospital,Zhengzhou,China from 2020 to 2023 were collected.Immunohistochemistry(IHC),fluorescence in situ hybridization(FISH)and DNA/RNA-based next-generation sequencing(NGS)were used to detect pan-TRK protein expression and fusion partner genes in tumors,and to further explore the correlation between pan-TRK staining patterns and partner genes.Results IHC and FISH were performed successfully in formalin-fixed paraffin-embedded tissues from 117 dMMR colorectal cancer patients.There were 15(15/117,12.8%)cases with positive pan-TRK,including 6 cases with strong staining in tumor cell membrane and cytoplasm,2 cases with weakly granular staining in tumor cytoplasm,2 cases with moderate dot-like staining in near 5%tumor cell nuclei,1 case with moderately to strongly granular staining in the cytoplasm and membrane of tumor cells,1 case with moderately to weakly granular staining in about 60%of the tumor cells,1 case with strongly staining in about 1%of the tumor cells,1 case with moderately to strongly staining in about 3%of the tumor cells and 1 case with diffuse,moderate para-nuclear dot-like and weakly perinuclear granular staining.NTRK1 gene disruption was detected in 6 cases(6/117,5.1%)and consistent with diffusely strong expression of pan-TRK.Based on DNA/RNA NGS,it was further confirmed that the 6 cases with NTRK1 gene disruption all carried TPM3-NTRK1 fusion gene,and all had high microsatellite instability and high tumor mutation burden.No KRAS,NRAS,BRAF V600E or TP53 gene mutations were detected.Four patients carried frame shift mutations in RNF43.Other molecular changes included 3 cases with ROS1 gene mutation,2 cases with BRAC,ALK,and EGFR gene mutations,2 cases with ATM gene mutation,and 2 c

关 键 词：结直肠肿瘤 DNA错配修复 免疫组织化学 基因融合 pan-TRK 

分 类 号：R735.34[医药卫生—肿瘤]