Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers
Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers
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DOI：
10.1172/jci85271
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发表时间：
2016-03-01
影响因子：
15.9
通讯作者：
Fagin, James A.
中科院分区：
文献类型：
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作者：
Lancia, Inigo;Ibrahimpasic, Tihana;Fagin, James A.
背景低分化甲状腺癌（PDTC）和间变性甲状腺癌（ATC）是一种罕见的、经常致死的肿瘤，迄今为止尚未对其进行全面的遗传学特征分析。我们对来自117例患者来源的PDTC和ATC的341个癌症基因进行了下一代测序，并分析了37种肿瘤的代表性子集的转录组。在甲状腺乳头状癌（PTC）的癌症基因组图谱研究（TCGA研究）的背景下分析结果。与PDTC相比，ATC具有更大的突变负荷，包括TP 53、TERT启动子、PI 3 K/AKT/mTOR通路效应子、SWI/SNF亚基和组蛋白甲基转移酶的突变频率更高。BRAF和RAS是主要的驱动因素，并决定了PDTC中淋巴结转移与远处转移的不同向性。RAS和BRAF分别在由都灵（PDTC-都灵）和MSKCC（PDTC-MSK）标准定义的PDTC之间进行了明显区分。翻译前起始复合物的一个组成部分ElF 1AX的突变在PDTC和ATC中显著富集，并且与RAS突变具有惊人的共现模式。虽然TERT启动子突变在PTC中是罕见的和亚克隆的，但它们在晚期癌症中是克隆的和高度流行的。应用TCGA衍生的BRAF-RAS评分（MAPK转录输出的测量）揭示了PDTC中与BRAF/RAS突变的关系，而ATC是BRAF样的，与驱动突变无关。这些数据支持一种肿瘤发生模型，其中PDTC和ATC通过关键的额外遗传异常的积累从分化良好的肿瘤中产生，其中许多具有预后和可能的治疗相关性。与PDTC相比，ATC中广泛的基因组破坏强调了其更大的毒力和更高的死亡率。
BACKGROUND. Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) are rare, and frequently lethal tumors that so far have not been subjected to comprehensive genetic characterization.METHODS. We performed next-generation sequencing of 341 cancer genes from 117 patient-derived PDTCs and ATCs and analyzed the transcriptome of a representative subset of 37 tumors. Results were analyzed in the context of The Cancer Genome Atlas study (TCGA study) of papillary thyroid cancers (PTC).RESULTS. Compared to PDTCs, ATCs had a greater mutation burden, including a higher frequency of mutations in TP53, TERT promoter, PI3K/AKT/mTOR pathway effectors, SWI/SNF subunits, and histone methyltransferases. BRAF and RAS were the predominant drivers and dictated distinct tropism for nodal versus distant metastases in PDTC. RAS and BRAF sharply distinguished between PDTCs defined by the Turin (PDTC-Turin) versus MSKCC (PDTC-MSK) criteria, respectively. Mutations of ElF1AX, a component of the translational preinitiation complex, were markedly enriched in PDTCs and ATCs and had a striking pattern of co-occurrence with RAS mutations. While TERT promoter mutations were rare and subclonal in PTCs, they were clonal and highly prevalent in advanced cancers. Application of the TCGA-derived BRAF-RAS score (a measure of MAPK transcriptional output) revealed a preserved relationship with BRAF/RAS mutation in PDTCs, whereas ATCs were BRAF-like irrespective of driver mutation.CONCLUSIONS. These data support a model of tumorigenesis where by PDTCs and ATCs arise from well-differentiated tumors through the accumulation of key additional genetic abnormalities, many of which have prognostic and possible therapeutic relevance. The widespread genomic disruptions in ATC compared with PDTC underscore their greater virulence and higher mortality.