Anaplastic thyroid cancer (ATC) represents one of the most lethal human cancers and although this tumor type is rare, ATC accounts for the majority of deaths from thyroid cancer. Due to the rarity of ATC, a comprehensive genomic characterization of this tumor type has been challenging, and thus the development of new therapies has been lacking. To date, there is only one mutation-driven targeted therapy for BRAF-mutant ATC. Recent genomic studies have used next generation sequencing to define the genetic landscape of ATC in order to identify new therapeutic targets. Together, these studies have confirmed the role of oncogenic mutations of MAPK pathway as key drivers of differentiated thyroid cancer (BRAF, RAS), and that additional genetic alterations in the PI3K pathway, TP53, and the TERT promoter are necessary for anaplastic transformation. Recent novel findings have linked the high mutational burden associated with ATC with mutations in the Mismatch Repair (MMR) pathway and overactivity of the AID/APOBEC family of cytidine deaminases. Additional novel mutations include cell cycle genes, SWI/SNF chromatin remodeling complex, and histone modification genes. Mutations in RAC1 were also identified in ATC, which have important implications for BRAF-directed therapies. In this review, we summarize these novel findings and the new genetic landscape of ATC. We further discuss the development of therapies targeting these pathways that are being tested in clinical and preclinical studies.

间变性甲状腺癌（ATC）代表人类最致命的癌症之一，尽管这种肿瘤类型很少见，但ATC占甲状腺癌死亡的大部分。由于ATC的稀有性，对该肿瘤类型的全面基因组表征一直是挑战性的，因此一直缺乏新疗法的开发。迄今为止，对于BRAF-突变ATC只有一种由突变驱动的靶向疗法。最近的基因组研究已使用下一代测序来定义ATC的遗传格局，以鉴定新的治疗靶标。总之，这些研究已证实MAPK途径的致癌突变是分化的甲状腺癌（BRAF，RAS）的关键驱动因素，并且在PI3K途径中还有其他遗传改变，TP53和TERT启动子是间变性转化所必需的。最近的新发现将与ATC相关的高突变负担与错配修复（MMR）途径中的突变以及胞苷脱氨基酶的AID / APOBEC家族的过度活跃联系在一起。其他新颖的突变包括细胞周期基因，SWI / SNF染色质重塑复合物和组蛋白修饰基因。在ATC中也发现了RAC1的突变，这对BRAF定向疗法具有重要意义。在这篇综述中，我们总结了这些新颖的发现和ATC的新遗传环境。我们将进一步讨论针对这些途径的疗法的开发，这些疗法正在临床和临床前研究中进行测试。