多基因突变检测在甲状腺穿刺细胞学辅助诊断中的应用  

Application of 9-gene panel in assisting fine needle aspiration cytology to diagnose thyroid cancer

作　　者：张彦祺 赵焕 赵琳琳 孙悦 王聪 张智慧 邱田 杨欣 肖汀 郭会芹 Zhang Yanqi;Zhao Huan;Zhao Linlin;Sun Yue;Wang Cong;Zhang Zhihui;Qiu Tian;Yang Xin;Xiao Ting;Guo Huiqin(Department of Pathology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;State Key Laboratory of Molecular Oncology,Department of Etiology and Carcinogenesis,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China)

机构地区：[1]国家癌症中心、国家肿瘤临床医学研究中心、中国医学科学院北京协和医学院肿瘤医院病理科,北京100021 [2]国家癌症中心、国家肿瘤临床医学研究中心、中国医学科学院北京协和医学院肿瘤医院分子肿瘤学国家重点实验室癌发生及预防分子机理北京市重点实验室,北京100021

出　　处：《中华肿瘤杂志》2024年第11期1049-1057,共9页Chinese Journal of Oncology

基　　金：新国家自然科学基金(81972804)。

摘　　要：目的评价9基因突变检测作为细胞学诊断不明确甲状腺病变的鉴别诊断方法和甲状腺细针穿刺细胞学检查的平行诊断方法的意义。方法2014年12月至2021年4月在中国医学科学院肿瘤医院行甲状腺细针穿刺细胞学检查的544例患者的579个甲状腺结节,收集其细胞学诊断后剩余的液基细胞学样本,采用下一代测序技术检测B-Raf原癌基因(BRAF)、成神经细胞瘤大鼠肉瘤病毒癌基因同源物(NRAS)、Harvey大鼠肉瘤病毒癌基因同源物(HRAS)、Kirsten大鼠肉瘤病毒癌基因同源物(KRAS)、肿瘤蛋白p53(TP53)、端粒酶逆转录酶(TERT)、磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α(PIK3CA)、鸟苷酸结合蛋白活性刺激肽(GNAS)和转染重排(RET)这9个基因任何癌症体细胞突变目录所收录位点的突变状态。以术后组织病理诊断和明确的细胞学诊断为金标准,比较9基因突变检测与BRAF V600E单基因检测的诊断效力。结果579个甲状腺结节中,细针穿刺细胞学诊断196个为BethesdaⅡ级,11个为BethesdaⅢ级,31个为BethesdaⅣ级,27个为BethesdaⅤ级,314个为BethesdaⅥ级;9基因突变检测阳性275个,突变率为47.5%。手术切除的329个甲状腺结节中,术后病理诊断30个为良性,5个为交界性,294个为恶性。将交界性结节视为恶性结节时,299个恶性结节中9基因的突变率由高到低依次为BRAF 62.21%(186/299),NRAS 5.02%(15/299),HRAS 1.00%(3/299),PIK3CA 0.67%(2/299),GNAS 0.67%(2/299),KRAS 0.33%(1/299),TP530.33%(1/299),TERT 0.33%(1/299),RET 0.00%(0/299)。9基因突变的恶性风险由高到低依次为BRAF 100%(186/186),PIK3CA 100.00%(2/2),GNAS 100.00%(2/2),TERT 100.00%(1/1),TP53100.00%(1/1),NRAS 78.95%(15/19),HRAS 75.00%(3/4),KRAS 50.00%(1/2)。对于细胞学诊断为BethesdaⅢ~Ⅳ级(诊断不明确)的甲状腺结节,9基因突变检测诊断甲状腺癌的灵敏度为34.48%(10/29),特异度为61.54%(8/13),准确率为42.86%(18/42),而BRAF V600E单基因检测诊断甲状腺癌的灵敏度�Objective To evaluate the utility of the 9-gene panel as a differential diagnostic method for thyroid nodules within determinate cytological diagnosis and as a parallel diagnostic method for thyroid fine-needle aspiration(FNA)cytology.Methods 579 liquid-based cytology samples from 544 patients were collected after thyroid FNA diagnosis in our hospital from December 2014 to April 2021.Mutations at any site of 9 genes,namely,BRAF,NRAS,HRAS,KRAS,GNAS,RET,TERT,TP53,and PIK3CA as recorded by the Catalogue of Somatic Mutations in Cancer(COSMIC),were analyzed by next-generation sequencing.Taking postoperative histopathology and cytology results with definite benign or malignant diagnosis as the gold standard,the diagnostic efficacy of the 9-gene panel as a reclassified method for thyroid nodules with indeterminate cytological diagnosis and as a parallel diagnostic method for thyroid FNA cytology were evaluated and compared with that of the BRAF V600E single-gene detection method.Results Of the 579 thyroid nodules,196(33.85%)were BethesdaⅡ,11(1.90%)were BethesdaⅢ,31(5.35%)were BethesdaⅣ,27(4.66%)were BethesdaⅤ,and 314(54.23%)were BethesdaⅥ,as diagnosed by thyroid FNA cytology.Among these 579 thyroid nodules,275 were tested positive for 9-gene mutations,with a mutation rate of 47.5%.Of the 329 thyroid nodules surgically removed,30(9.12%)were benign,5(1.52%)were borderline,and 294(89.36%)were malignant.Regarding borderline nodules as malignant nodules,the mutation rates of the 9 genes in the 299 malignant thyroid nodules from high to low were BRAF 62.21%(186/299),NRAS 5.02%(15/299),HRAS 1.00%(3/299),PIK3CA 0.67%(2/299),GNAS 0.67%(2/299),KRAS 0.33%(1/299),TP530.33%(1/299),TERT 0.33%(1/299)and RET 0.00%(0/299).The malignant risks of the 9 genes from high to low were BRAF 100%(186/186),PIK3CA 100.00%(2/2),GNAS 100.00%(2/2),TERT 100.00%(1/1),TP53100.00%(1/1),NRAS 78.95%(15/19),HRAS 75.00%(3/4),and KRAS 50.00%(1/2).For thyroid nodules of BethesdaⅢ-Ⅳ(indeterminate diagnosis),the sensitivity(SN)of the 9-gene panel i

关 键 词：甲状腺肿瘤 细针穿刺术 细胞学 基因突变检测 诊断 

分 类 号：R736.1[医药卫生—肿瘤]