TERT Promoter Mutations and Their Association with BRAF V600E Mutation and Aggressive Clinicopathological Characteristics of Thyroid Cancer
TERT Promoter Mutations and Their Association with BRAF V600E Mutation and Aggressive Clinicopathological Characteristics of Thyroid Cancer
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DOI：
10.1210/jc.2013-4048
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发表时间：
2014-06-01
影响因子：
5.8
通讯作者：
Xing, Mingzhao
中科院分区：
文献类型：
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作者：
Liu, Xiaoli;Qu, Shen;Xing, Mingzhao
背景：端粒酶逆转录酶（TERT）基因的启动子突变chr5:1,295,228C>T和chr5:1,295,250C>T（分别称为C228T和C250T）已在多种癌症中报道，需要在甲状腺癌中进一步研究。目的：探讨各种甲状腺肿瘤中TERT启动子突变，并探讨其与BRAF V600E突变、碘摄入及甲状腺癌临床病理行为的关系。设计：通过对中国正常和高碘地区原发性甲状腺肿瘤的基因组DNA测序，鉴定TERT启动子和BRAF突变，并分析其临床病理相关性。结果：9.6%（39 / 408）的乳头状甲状腺癌（PTC）中存在C228T突变，1.7%（7 / 408）的PTC中存在C250T突变，11.3%（46 / 408）的PTC中存在C250T突变。C228T占31.8%（22例中7例），C250T占4.6%（22例中1例），二者共占36.4%（22例中8例）。44例良性甲状腺肿瘤未发现TERT突变。这两种突变发生在BRAF突变阴性PTC的3.8%（158例中的6例）和BRAF突变阳性PTC的16.0%（250例中的40例）（P = 5.87 × 10(-4)），表明它们之间存在关联。与BRAF突变不同，TERT启动子突变与高碘摄入无关，但与患者年龄较大、肿瘤大小较大、甲状腺外侵袭和晚期III/IV期PTC相关。同时存在的TERT和BRAF突变与临床病理侵袭性的关系更为普遍和显著。结论：在这个大型队列中，我们发现TERT启动子突变是常见的，特别是在FTC和BRAF突变阳性的PTC中，并且与侵袭性临床病理特征相关。
Context: Promoter mutations chr5:1,295,228C>T and chr5:1,295,250C>T (termed C228T and C250T, respectively) in the gene for telomerase reverse transcriptase (TERT) have been reported in various cancers and need to be further investigated in thyroid cancer.Objective: The aim of the study was to explore TERT promoter mutations in various thyroid tumors and examine their relationship with BRAF V600E mutation, iodine intake, and clinicopathological behaviors of thyroid cancer.Design: TERT promoter and BRAF mutations were identified by sequencing genomic DNA of primary thyroid tumors from normal-and high-iodine regions in China, and clinicopathological correlation was analyzed.Results: The C228T mutation was found in 9.6% (39 of 408) of papillary thyroid cancer (PTC), C250T was found in 1.7% (7 of 408) of PTC, and they were collectively found in 11.3% (46 of 408) of PTC. C228T was found in 31.8% (7 of 22) and C250T in 4.6% (1 of 22) of follicular thyroid cancer (FTC), and they were collectively found in 36.4% (8 of 22) of FTC. No TERT mutation was found in 44 benign thyroid tumors. The two mutations occurred in 3.8% (6 of 158) of BRAF mutation-negative PTC vs 16.0% (40 of 250) of BRAF mutation-positive PTC (P = 5.87 x 10(-4)), demonstrating their association. Unlike BRAF mutation, TERT promoter mutations were not associated with high iodine intake, but they were associated with older patient age, larger tumor size, extrathyroidal invasion, and advanced stages III/IV of PTC. Coexisting TERT and BRAF mutations were even more commonly and more significantly associated with clinicopathological aggressiveness.Conclusions: In this large cohort, we found TERT promoter mutations to be common, particularly in FTC and BRAF mutation-positive PTC, and associated with aggressive clinicopathological characteristics.