Li Lu, Zhang Likun, Jiang Wenhao, Gui Zhiqiang, Wang Zhihong, Zhang Hao, He Yi, Zhu Yi, Guo Tiannan, Guan Haixia, Liu Zhiyan, Sun Yaoting, Gao Jianqing
College of Pharmaceutical Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, China.
State Key Laboratory of Advanced Drug Delivery and Release Systems, College of Pharmaceutical Sciences, Zhejiang University, No. 866 Yuhangtang Road, Hangzhou, 310058, China.
Endocr Pathol. 2024 Dec;35(4):442-452. doi: 10.1007/s12022-024-09834-z. Epub 2024 Nov 4.
Oncocytic thyroid tumors are characterized by an elevated mitochondrial density within the cells, distinguishing them from other thyroid tumors, exhibit distinct clinical behaviors, including increased invasiveness and iodine therapy resistance. However, the proteomic alterations in oncocytic thyroid tumors remain inadequately characterized. In this study, we analyzed 156 Asian patients with oncocytic thyroid adenomas (OA) and carcinomas (OCA) to explore their clinical, genetic, and proteomic features. Genetic testing of 73 samples revealed frequent mutations in TERT, NRAS, EIF1AX, EZH1, and HRAS, with TERT promoter mutations being exclusive to OCAs. Proteomic analysis identified 66 mitochondrial-specific proteins significantly highly expressed in oncocytic tumors than in non-oncocytic tumors. This led to the development of a thyroid oncocytic score (TOS) to quantify oncocytic characteristics. Among these proteins, isocitrate dehydrogenase 2 (IDH2) was substantially overexpressed in oncocytic tumors and further confirmed by immunohistochemistry in oncocytic tumor slides (n = 41) and non-oncocytic tumor slides (n = 40). Moreover, IDH2 is significantly overexpressed in OCA compared to OA highlighting its potential as a biomarker for differential diagnosis of oncocytic tumors and malignancy. These findings improve the understanding of oncocytic thyroid tumors molecular pathology and suggest IDH2 as a valuable marker for clinical management.
嗜酸性甲状腺肿瘤的特征是细胞内线粒体密度升高，这使其有别于其他甲状腺肿瘤，且表现出独特的临床行为，包括侵袭性增加和对碘治疗耐药。然而，嗜酸性甲状腺肿瘤中的蛋白质组学改变仍未得到充分表征。在本研究中，我们分析了156例亚洲嗜酸性甲状腺腺瘤（OA）和癌（OCA）患者，以探索其临床、遗传和蛋白质组学特征。对73份样本的基因检测发现TERT、NRAS、EIF1AX、EZH1和HRAS频繁突变，其中TERT启动子突变仅见于OCA。蛋白质组学分析确定了66种线粒体特异性蛋白质在嗜酸性肿瘤中比在非嗜酸性肿瘤中显著高表达。这促使我们开发了一种甲状腺嗜酸性评分（TOS）来量化嗜酸性特征。在这些蛋白质中，异柠檬酸脱氢酶2（IDH2）在嗜酸性肿瘤中大量过表达，并在嗜酸性肿瘤切片（n = 41）和非嗜酸性肿瘤切片（n = 40）中通过免疫组织化学进一步证实。此外，与OA相比，IDH2在OCA中显著过表达，突出了其作为嗜酸性肿瘤和恶性肿瘤鉴别诊断生物标志物的潜力。这些发现增进了对嗜酸性甲状腺肿瘤分子病理学的理解，并表明IDH2是临床管理中有价值的标志物。
