The genetics underlying thyroid cancer dedifferentiation is only partly understood and has not yet been characterised using comprehensive pan-genomic analyses. We investigated a unique case with synchronous follicular thyroid carcinoma (FTC), poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC), as well as regional lymph node metastases from the PDTC and ATC from a single patient using whole-genome sequencing (WGS). The FTC displayed mutations in CALR, RB1, and MSH2, and the PDTC exhibited mutations in TP53, DROSHA, APC, TERT, and additional DNA repair genes - associated with an immense increase in sub-clonal somatic mutations. All components displayed an overrepresentation of C>T transitions with associated microsatellite instability (MSI) in the PDTC and ATC, with borderline MSI in the FTC. Clonality analyses pinpointed a shared ancestral clone enriched for mutations in TP53-associated regulation of DNA repair and identified important sub-clones for each tumour component already present in the corresponding preceding lesion. This genomic characterisation of the natural progression of thyroid cancer reveals several novel genes of interest for future studies. Moreover, the findings support the theory of a stepwise dedifferentiation process and suggest that defects in DNA repair could play an important role in the clonal evolution of thyroid cancer. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

中文翻译：

---

同步甲状腺癌的全基因组测序可确定甲状腺癌去分化中异常的DNA修复。

甲状腺癌去分化的潜在遗传学仅得到部分了解，尚未使用全面的全基因组分析进行表征。我们调查了一个独特的病例，该病例患有同步性滤泡性甲状腺癌（FTC），低分化甲状腺癌（PDTC）和间变性甲状腺癌（ATC），以及来自单个患者使用全基因组的PDTC和ATC的区域淋巴结转移排序（WGS）。FTC在CALR，RB1和MSH2中显示突变，而PDTC在TP53，DROSHA，APC，TERT和其他DNA修复基因中显示突变-与亚克隆体细胞突变的大量增加相关。在PDTC和ATC中，所有组件均显示了C> T跃迁的相关超微卫星不稳定性（MSI），而在FTC中，MSI处于临界边界。克隆性分析指出了一个共享的祖先克隆，该克隆富集了与TP53相关的DNA修复调控中的突变，并为相应的先前病变中已经存在的每个肿瘤成分确定了重要的亚克隆。甲状腺癌自然进展的这种基因组学特征揭示了一些新的感兴趣的基因，有待进一步研究。此外，这些发现支持逐步去分化过程的理论，并暗示DNA修复中的缺陷可能在甲状腺癌的克隆进化中起重要作用。©2019英国和爱尔兰病理学会。由John Wiley＆Sons，Ltd.出版