Molecular Determinants of Thyroid Nodules with Indeterminate Cytology andRASMutations
Molecular Determinants of Thyroid Nodules with Indeterminate Cytology andRASMutations
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DOI：
10.1089/thy.2019.0650
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发表时间：
2020-08-25
期刊：
影响因子：
6.6
通讯作者：
Chung, Christine H.
中科院分区：
文献类型：
--
作者：
Hernandez-Prera, Juan C.;Valderrabano, Pablo;Chung, Christine H.
背景：RAS基因家族突变是细胞学不确定的甲状腺结节中最常见的突变，存在于广泛的组织学诊断中。我们评估了RAS突变结节在组织学/临床范围内的差异表达基因和信号通路，以确定与高恶性风险相关的关键分子决定因素。方法：对61例RAS基因突变的甲状腺结节进行鉴定。根据组织学诊断和生物学行为，将结节分为五类，分别为非肿瘤性外观、良性肿瘤、不确定的恶性潜能、低危癌或高危癌。免疫组织化学染色检测血管生成素-2表达水平。结果：以5类基因为监测参数，对差异表达基因进行分析，发现恶性程度与细胞周期和细胞凋亡相关基因(Bax、CCNE2、CDKN2A、CDKN2B、CHEK1、E2F1、GSK3B、NFKB1和PRKAR2A)、PI3K通路(CCNE2、CSF3、GSKB3、NFKB1、PPP2R2C和SGK2)和基质因子(ANGPT2和DLL4)显著相关。免疫组织化学检测血管生成素-2的表达也显示出从非肿瘤性表现到高危性癌表达增加的趋势(p<；0.0001)。结论：RAS突变甲状腺结节的基因表达分析表明，关键致癌途径的上调取决于其恶性程度，并支持循序渐进的概念。ANGPT2表达作为一种潜在的诊断生物标志物的价值值得进一步评估。
Background:RASgene family mutations are the most prevalent in thyroid nodules with indeterminate cytology and are present in a wide spectrum of histological diagnoses. We evaluated differentially expressed genes and signaling pathways across the histological/clinical spectrum ofRAS-mutant nodules to determine key molecular determinants associated with a high risk of malignancy. Methods:Sixty-one thyroid nodules withRASmutations were identified. Based on the histological diagnosis and biological behavior, the nodules were grouped into five categories indicating their degree of malignancy: non-neoplastic appearance, benign neoplasm, indeterminate malignant potential, low-risk cancer, or high-risk cancer. Gene expression profiles of these nodules were determined using the NanoString PanCancer Pathways and IO 360 Panels, and Angiopoietin-2 level was determined by immunohistochemical staining. Results:The analysis of differentially expressed genes using the five categories as supervising parameters unearthed a significant correlation between the degree of malignancy and genes involved in cell cycle and apoptosis (BAX,CCNE2,CDKN2A,CDKN2B,CHEK1,E2F1,GSK3B,NFKB1, andPRKAR2A),PI3Kpathway (CCNE2,CSF3,GSKB3,NFKB1,PPP2R2C, andSGK2), and stromal factors (ANGPT2andDLL4). The expression of Angiopoietin-2 by immunohistochemistry also showed the same trend of increasing expression from non-neoplastic appearance to high-risk cancer (p < 0.0001). Conclusions:The gene expression analysis ofRAS-mutant thyroid nodules suggests increasing upregulation of key oncogenic pathways depending on their degree of malignancy and supports the concept of a stepwise progression. The utility ofANGPT2expression as a potential diagnostic biomarker warrants further evaluation.