Unidade de Investigação em Patobiologia Molecular (J.M.P., I.F.F., M.M.M., V.L., B.M.C.) and Serviço de Endocrinologia (V.L.), Instituto Português de Oncologia de Lisboa Francisco Gentil, 1099-023 Lisboa, Portugal; and Centro de Estudos de Doenças Crónicas (J.M.P., I.F.F., M.M.M., V.L., B.M.C.), Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal.
J Clin Endocrinol Metab. 2014 Mar;99(3):E497-507. doi: 10.1210/jc.2013-1512. Epub 2014 Jan 13.
Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment.
In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets.
We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (β-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs).
Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-β pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-β-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected.
Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-β pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment.
间变性甲状腺癌（ATC）是最致命的恶性肿瘤之一，目前尚无有效的治疗方法。
本研究旨在阐明导致 ATC 发生的分子改变，并确定新的治疗靶点。
我们对 5 例 ATC 进行了全基因组基因表达谱分析，并通过定量 RT-PCR 在独立的肿瘤样本中验证了差异表达的基因。在 26 例 ATC 中，我们搜索了参与最失调细胞过程的基因中的致病改变，包括 RAS、BRAF、TP53、CTNNB1（β-连环蛋白）和 PIK3CA 基因的热点区域，以及细胞周期成分的全面分析[细胞周期蛋白依赖性激酶（CDK）抑制剂（CDKI）：CDKN1A（p21（CIP1））；CDKN1B（p27（KIP1））；CDKN2A（p14（ARF），p16（INK4A））；CDKN2B（p15（INK4B））；CDKN2C（p18（INK4C））]、细胞黏附（AXIN1）和增殖（PTEN）。还对 22 例低分化甲状腺癌（PDTC）进行了突变分析。
表达谱分析显示，ATC 的特征是上皮成分表达下调，间充质标记物和 TGF-β 通路基因上调，以及细胞周期相关基因表达上调。因此，验证了 TGF-β 反应性间充质因子 SNAI2 基因的上调。CDKN3 可阻止 G1/S 期转换，在 ATC 和 PDTC 中显著上调，并在 ATC 中异常剪接。突变分析显示，大多数突变存在于 TP53（42%的 ATC；27%的 PDTC）或 RAS（31%的 ATC；18%的 PDTC）中。TP53 和 RAS 改变显示出相互排斥的证据（P =.0354）。PIK3CA、PTEN 和 CDKI 突变存在于 14%-20%的 PDTC 中，10%-14%的 ATC 中。BRAF、CTNNB1 和 AXIN1 突变很少检测到。
总的来说，这项研究确定了 TP53、RAS、CDKI 和 TGF-β 通路的关键作用，这可能代表 ATC 和 PDTC 治疗的可行治疗靶点。
