目的:RAS突变代表甲状腺癌中常见的驱动改变。它们可以在良性的,具有滤泡结构的低风险和恶性甲状腺肿瘤,通常在术前细胞学上诊断为不确定的结节。因此,术前检测RAS突变对恶性肿瘤的预测价值欠佳.在这项研究中,我们研究了滤泡结构携带RAS基因突变的良性和恶性甲状腺肿瘤中差异表达的microRNA(miRNA).
方法:从60个RAS突变的滤泡型甲状腺肿瘤中纯化总RNA,包括滤泡性腺瘤(FA),具有乳头状样核特征的非侵袭性滤泡性甲状腺肿瘤(NIFTP),乳头状和滤泡性甲状腺癌病例(PTC,FTC);22个RAS阴性FA用作对照。通过数字计数(nCounternanoString平台)进行798个miRNA的表达分析。
结果:比较RAS突变型和RAS阴性FAs,12个miRNAs显示出显著的失调,这可能与RAS突变的致癌效应有关。22个miRNA在RAS突变型良性肿瘤和恶性肿瘤中差异表达。考虑到肿瘤类型,24个miRNAs在PTC中表达下调,19在NIFTP中,FTC和7个,与FA组相比;其中,miR-146b-5p,miR-144-3p,和miR-451a在所有比较中显示一致的失调,倍数变化最高.
结论:滤泡型甲状腺肿瘤的miRNA表达分析表明RAS突变影响良性肿瘤的miRNA谱。此外,一些miRNAs显示出组织型特异性失调,可以区分RAS突变型良性和RAS突变型恶性甲状腺病变,因此值得进一步研究作为潜在的诊断标志物。
OBJECTIVE: RAS mutations represent common driver alterations in thyroid cancer. They can be found in benign, low-risk and malignant thyroid tumors with follicular architecture, which are often diagnosed as indeterminate nodules on preoperative cytology. Therefore, the detection of RAS mutations in preoperative setting has a suboptimal predictive value for malignancy. In this study, we investigated differentially expressed microRNA (miRNA) in benign and malignant thyroid tumors with follicular architecture carrying mutations in RAS genes.
METHODS: Total RNA was purified from 60 RAS-mutant follicular-patterned thyroid tumors, including follicular adenoma (FA), noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), papillary and follicular thyroid carcinoma cases (PTC, FTC); 22 RAS-negative FAs were used as controls. The expression analysis of 798 miRNAs was performed by digital counting (nCounter nanoString platform).
RESULTS: Comparing RAS-mutant and RAS-negative FAs, 12 miRNAs showed significant deregulation, which was likely related to the oncogenic effects of RAS mutations. Twenty-two miRNAs were differentially expressed in RAS-mutant benign versus malignant tumors. Considering the tumor type, 24 miRNAs were deregulated in PTC, 19 in NIFTP, and seven in FTC and compared to FA group; among these, miR-146b-5p, miR-144-3p, and miR-451a showed consistent deregulation in all the comparisons with the highest fold change.
CONCLUSIONS: The miRNA expression analysis of follicular-patterned thyroid tumors demonstrated that RAS mutations influences miRNA profile in benign tumors. In addition, several miRNAs showed a histotype-specific deregulation and could discriminate between RAS-mutant benign and RAS-mutant malignant thyroid lesions, thus deserving further investigation as potential diagnostic markers.