Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, 03080, Republic of Korea.
Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, 08826, Republic of Korea.
Nat Commun. 2019 Jun 24;10(1):2764. doi: 10.1038/s41467-019-10680-5.
Anaplastic thyroid cancer (ATC) and advanced differentiated thyroid cancers (DTCs) show fatal outcomes, unlike DTCs. Here, we demonstrate mutational landscape of 27 ATCs and 86 advanced DTCs by massively-parallel DNA sequencing, and transcriptome of 13 ATCs and 12 advanced DTCs were profiled by RNA sequencing. TERT, AKT1, PIK3CA, and EIF1AX were frequently co-mutated with driver genes (BRAF and RAS) in advanced DTCs as well as ATC, but tumor suppressors (e.g., TP53 and CDKN2A) were predominantly altered in ATC. CDKN2A loss was significantly associated with poor disease-specific survival in patients with ATC or advanced DTCs, and up-regulation of CD274 (PD-L1) and PDCD1LG2 (PD-L2). Transcriptome analysis revealed a fourth molecular subtype of thyroid cancer (TC), ATC-like, which hardly reflects the molecular signatures in DTC. Furthermore, the activation of JAK-STAT signaling pathway could be a potential druggable target in RAS-positive ATC. Our findings provide insights for precision medicine in patients with advanced TCs.
间变性甲状腺癌 (ATC) 和晚期分化型甲状腺癌 (DTC) 的结局是致命的，与 DTC 不同。在这里，我们通过大规模平行 DNA 测序展示了 27 例 ATC 和 86 例晚期 DTC 的突变图谱，并通过 RNA 测序对 13 例 ATC 和 12 例晚期 DTC 的转录组进行了分析。在晚期 DTC 以及 ATC 中，TERT、AKT1、PIK3CA 和 EIF1AX 与驱动基因 (BRAF 和 RAS) 经常共同发生突变，但肿瘤抑制基因 (如 TP53 和 CDKN2A) 在 ATC 中主要发生改变。CDKN2A 缺失与 ATC 或晚期 DTC 患者的疾病特异性生存率显著相关，CD274 (PD-L1) 和 PDCD1LG2 (PD-L2) 的上调。转录组分析揭示了甲状腺癌 (TC) 的第四种分子亚型，即 ATC 样型，它几乎不能反映 DTC 中的分子特征。此外，JAK-STAT 信号通路的激活可能是 RAS 阳性 ATC 的一个潜在治疗靶点。我们的研究结果为晚期 TCs 患者的精准医学提供了思路。
