摘要目的:探讨RAS基因在甲状腺滤泡分化肿瘤中的突变及意义。方法:收集2000年1月至2017年12月北京市顺义区医院207例甲状腺滤泡分化肿瘤患者的样本及临床资料，包括60例滤泡亚型甲状腺乳头状癌（FVPTC）、42例经典型甲状腺乳头状癌（CPTC）、26例滤泡性甲状腺癌（FTC）、40例滤泡性甲状腺腺瘤（FTA）和39例腺瘤样增生。应用免疫组织化学染色法检测BRAF V600E的突变情况，将FVPTC分为BRAF样（BRAF V600E突变者）和RAS样（无BRAF V600E突变者）；应用即时荧光定量聚合酶链反应法检测RAS样FVPTC、CPTC、FTC、FTA和腺瘤样增生中RAS基因的突变情况，分析比较它们之间RAS基因突变的差异及其与临床病理学特征的相关性。结果:甲状腺滤泡分化良、恶性肿瘤平均年龄分别为53.2岁和47.7岁，其中男性42例，女性165例，大多数肿瘤最大径≤4 cm；恶性病变的甲状腺周围扩散少见，多数处于Ⅰ、Ⅱ期。FTC中肿瘤直径明显大于RAS样FVPTC组和CPTC组（ P均<0.01）。RAS样FVPTC、CPTC和FTC三组中甲状腺周围扩散少见，但FTC组临床分期明显高于RAS样FVPTC组（ P<0.01）和CPTC组（ P<0.01）。即时荧光定量聚合酶链反应结果显示，RAS基因的突变率FTC组最高（61.5%），明显高于其他组（ P均<0.01）；CPTC中最低，仅为4.8%，而在RAS样FVPTC、FTA和腺瘤样增生中突变率相当（15%左右）。Spearman秩相关分析结果表明，RAS基因突变与良性肿瘤（FTA和腺瘤样增生）的发病年龄、性别和肿瘤大小以及与恶性肿瘤（RAS样FVPTC、CPTC和FTC）的发病年龄、性别、肿瘤大小、淋巴结转移、甲状腺周围扩散和临床分期均无相关性。 结论:RAS基因突变在甲状腺滤泡分化的良、恶性肿瘤中均可发生，以FTC中最高，鉴别诊断时要结合形态及免疫组织化学以及其他分子变化综合考虑。RAS样FVPTC分子遗传学更接近于FTA和腺瘤样增生。RAS基因突变不是甲状腺疾病的预后影响因子。

abstractsObjective:To investigate the frequency and clinical significance of RAS mutation in thyroid tumors with follicular differentiation.Methods:The samples and clinical data of 207 patients with thyroid follicular-differentiated tumors were collected at Shunyi Region Hospital of Beijing from January 2000 to December 2017, including 60 cases of follicular variant of papillary thyroid carcinoma (FVPTC), 42 cases of classical papillary thyroid carcinoma (CPTC), 26 cases of follicular thyroid carcinoma (FTC), 40 cases of follicular adenoma (FTA) and 39 cases of adenomatoid hyperplasia. BRAF V600E mutations were detected using immunohistochemical staining. FVPTC was divided into BRAF-like (BRAF V600E mutant) and RAS-like (without BRAF V600E mutant). Real-time fluorescence quantitative polymerase chain reaction was used to detect the RAS mutation in RAS-like FVPTC, CPTC, FTC, FTA and adenomatoid hyperplasia. The genetic differences in RAS mutation and their correlation with clinicopathological features were analyzed.Results:The average age of patients with benign and malignant tumors in thyroid with follicular differentiation was 53.2 years and 47.7 years, respectively. In these patients, 42 were male and165 were female. Most of the tumors had a maximum diameter of less than 4 cm, and rarely spread to the surrounding tissues of thyroid and were at early stage (stages Ⅰ and Ⅱ). The diameter of tumors in FTC was significantly larger than that in RAS-like FVPTC and CPTC groups ( P<0.01). Peripheral thyroid invasion was rare in the RAS-like FVPTC, CPTC and FTC groups, but the clinical stage of FTC was more advanced than that of RAS-like FVPTC group ( P<0.01) or CPTC group ( P<0.01). The real-time fluorescence quantitative PCR showed that the RAS mutation rate in FTC was the highest (61.5%), significantly higher than that in others ( P<0.01). The RAS mutation rate in CPTC was the lowest (4.8%), while those in RAS-like FVPTC, FTA and adenomatous hyperplasia were similar (about 15%). The Spearman rank correlation analysis showed that the RAS mutation was not correlated with age, sex or tumor size in benign lesions (FTA and adenomatous hyperplasia), nor was it associated with age, sex, tumor size, lymph node metastasis, spreading of tumors to thyroid and clinical stage in malignant tumors (RAS-like FVPTC, CPTC and FTC). Conclusions:RAS mutation can occur in both benign and malignant thyroid tumors with follicular differentiation, in which the incidence is the highest in FTC. Both morphologic and immunohistochemical changes should be taken into account. The molecular genetics of RAS-like FVPTC is similar to FTA and adenomatous hyperplasia. RAS gene mutation appears not to be a prognostic factor for thyroid diseases.