Landa Iñigo, Ibrahimpasic Tihana, Boucai Laura, Sinha Rileen, Knauf Jeffrey A, Shah Ronak H, Dogan Snjezana, Ricarte-Filho Julio C, Krishnamoorthy Gnana P, Xu Bin, Schultz Nikolaus, Berger Michael F, Sander Chris, Taylor Barry S, Ghossein Ronald, Ganly Ian, Fagin James A
J Clin Invest. 2016 Mar 1;126(3):1052-66. doi: 10.1172/JCI85271. Epub 2016 Feb 15.
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.
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).
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 EIF1AX, 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.
These data support a model of tumorigenesis whereby 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.
This work was supported in part by NIH grants CA50706, CA72597, P50-CA72012, P30-CA008748, and 5T32-CA160001; the Lefkovsky Family Foundation; the Society of Memorial Sloan Kettering; the Byrne fund; and Cycle for Survival.
低分化甲状腺癌（PDTC）和未分化甲状腺癌（ATC）是罕见且通常致命的肿瘤，迄今为止尚未进行全面的基因特征分析。
我们对117例源自患者的PDTC和ATC进行了341个癌症基因的二代测序，并分析了37个肿瘤的代表性亚组的转录组。在甲状腺乳头状癌（PTC）的癌症基因组图谱研究（TCGA研究）背景下分析结果。
与PDTC相比，ATC具有更高的突变负担，包括TP53、TERT启动子、PI3K/AKT/mTOR信号通路效应器、SWI/SNF亚基和组蛋白甲基转移酶的更高突变频率。BRAF和RAS是主要驱动因素，并决定了PDTC中淋巴结转移与远处转移的不同倾向性。RAS和BRAF分别在由都灵（PDTC-都灵）与MSKCC（PDTC-MSK）标准定义的PDTC之间有明显区别。翻译起始前复合物的一个组成部分EIF1AX的突变在PDTC和ATC中显著富集，并且与RAS突变有显著的共现模式。虽然TERT启动子突变在PTC中罕见且为亚克隆，但在晚期癌症中它们是克隆性的且高度普遍。应用源自TCGA的BRAF-RAS评分（一种MAPK转录输出的衡量指标）显示，其与PDTC中的BRAF/RAS突变保持着一定关系，而ATC无论驱动突变如何均类似BRAF型。
这些数据支持一种肿瘤发生模型，即PDTC和ATC通过关键的额外基因异常积累，从高分化肿瘤发展而来，其中许多异常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突出了它们更强的毒性和更高的死亡率。
本研究部分得到美国国立卫生研究院（NIH）资助项目CA50706、CA72597、P50-CA72012、P30-CA008748和5T32-CA160001；列夫科夫斯基家族基金会；纪念斯隆凯特琳癌症中心协会；伯恩基金；以及生存循环组织的支持。
