Liu Rengyun, Xing Mingzhao
Laboratory for Cellular and Molecular Thyroid ResearchDivision of Endocrinology, Diabetes and Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA.
Laboratory for Cellular and Molecular Thyroid ResearchDivision of Endocrinology, Diabetes and Metabolism, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, Maryland 21287, USA
Endocr Relat Cancer. 2016 Mar;23(3):R143-55. doi: 10.1530/ERC-15-0533. Epub 2016 Jan 5.
The 2013 discovery of Telomerase reverse transcriptase (TERT) promoter mutations chr5, 1,295,228 C>T (C228T) and 1,295,250 C>T (C250T) in thyroid cancer represents an important event in the thyroid cancer field and much progress has occurred since then. This article provides a comprehensive review of this exciting new thyroid cancer field. The oncogenic role of TERT promoter mutations involves their creation of consensus binding sites for E-twenty-six transcriptional factors. TERT C228T is far more common than TERT C250T and their collective prevalence is, on average, 0, 11.3, 17.1, 43.2 and 40.1% in benign thyroid tumors, papillary thyroid cancer (PTC), follicular thyroid cancer, poorly differentiated thyroid cancer and anaplastic thyroid cancer, respectively, displaying an association with aggressive types of thyroid cancer. TERT promoter mutations are associated with aggressive thyroid tumor characteristics, tumor recurrence and patient mortality as well as BRAF V600E mutation. Coexisting BRAF V600E and TERT promoter mutations have a robust synergistic impact on the aggressiveness of PTC, including a sharply increased tumor recurrence and patient mortality, while either mutation alone has a modest impact. Thus, TERT with promoter mutations represents a prominent new oncogene in thyroid cancer and the mutations are promising new diagnostic and prognostic genetic markers for thyroid cancer, which, in combination with BRAF V600E mutation or other genetic markers (e.g. RAS mutations), are proving to be clinically useful for the management of thyroid cancer. Future studies will specifically define such clinical utilities, elucidate the biological mechanisms and explore the potential as therapeutic targets of TERT promoter mutations in thyroid cancer.
2013年在甲状腺癌中发现端粒酶逆转录酶（TERT）启动子突变chr5、1,295,228 C>T（C228T）和1,295,250 C>T（C250T），这是甲状腺癌领域的一个重要事件，自那时起已经取得了很大进展。本文全面综述了这个令人兴奋的甲状腺癌新领域。TERT启动子突变的致癌作用涉及它们为E-26转录因子创造共有结合位点。TERT C228T比TERT C250T常见得多，它们在良性甲状腺肿瘤、乳头状甲状腺癌（PTC）、滤泡状甲状腺癌、低分化甲状腺癌和未分化甲状腺癌中的总体患病率分别平均为0%、11.3%、17.1%、43.2%和40.1%，显示出与侵袭性甲状腺癌类型相关。TERT启动子突变与侵袭性甲状腺肿瘤特征、肿瘤复发和患者死亡率以及BRAF V600E突变相关。BRAF V600E和TERT启动子突变共存对PTC的侵袭性有强烈的协同影响，包括肿瘤复发和患者死亡率急剧增加，而单独任何一种突变的影响都较小。因此，具有启动子突变的TERT是甲状腺癌中一个突出的新致癌基因，这些突变是甲状腺癌有前景的新诊断和预后遗传标志物，与BRAF V600E突变或其他遗传标志物（如RAS突变）结合，已被证明在甲状腺癌管理中具有临床实用性。未来的研究将具体确定此类临床实用性，阐明生物学机制，并探索TERT启动子突变作为甲状腺癌治疗靶点的潜力。
