Highly prevalent TERT promoter mutations in aggressive thyroid cancers.
Highly prevalent TERT promoter mutations in aggressive thyroid cancers.
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DOI：
10.1530/erc-13-0210
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发表时间：
2013-08
影响因子：
3.9
通讯作者：
Xing M
中科院分区：
文献类型：
--
作者：
Liu X;Bishop J;Shan Y;Pai S;Liu D;Murugan AK;Sun H;El-Naggar AK;Xing M
突变1 295 228 C>T和1 295 250 C>T（分别称为C228 T和C250 T），对应于端粒酶逆转录酶（TERT）基因启动子翻译起始位点的−124 C>T和−146 C>T，最近在人类癌症中有报道，但尚未在甲状腺癌中报道。我们通过对大量原发性肿瘤样本进行基因组测序来探索甲状腺癌中的这些突变。我们在0/85中发现了C228 T突变（0.0%）良性甲状腺肿瘤，30/257（11.7%）乳头状甲状腺癌（PTC），9/79（11.4%）滤泡性甲状腺癌（FTC），8例中有3例（37.5%）低分化甲状腺癌（PDTC），23/54（42.6%）间变性甲状腺癌（ATC），8/12（66.7%）甲状腺癌细胞系。C250 T突变并不常见，但与C228 T突变相互排斥，这两种突变共同见于79个FTC中的11个（13.9%）、54个ATC中的25个（46.3%）和12个甲状腺癌细胞系中的11个（91.7%）。在PTC变异体中，C228 T突变在13例高细胞PTC（TCPTC）中的4例（30.8%）、187例常规PTC中的23例（12.3%）和56例滤泡型PTC样本中的2例（3.6%）中发现。16例甲状腺髓样癌标本中未发现TERT突变。C228 T突变与PTC中的BRAF V600 E突变相关，存在于104例BRAF突变阳性PTC中的19例（18.3%）与153例BRAF突变阴性PTC样本中的11例（7.2%）（P=0.0094）。相反，在30例C228 T突变阳性PTC中有19例（63.3%）发现BRAF突变，而在227例C228 T突变阴性PTC样本中有85例（37.4%）发现BRAF突变（P=0.0094）。因此，据我们所知，我们第一次证明了甲状腺癌中的TERT启动子突变，这在侵袭性甲状腺癌TCPTC，PDTC，ATC和BRAF突变阳性PTC中特别普遍，揭示了甲状腺癌的新遗传背景。
Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to −124 C>T and −146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.