Whole-genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
Whole-genome sequencing of synchronous thyroid carcinomas identifies aberrant DNA repair in thyroid cancer dedifferentiation
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DOI：
10.1002/path.5359
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发表时间：
2019-11-29
影响因子：
7.3
通讯作者：
Juhlin, C. Christofer
中科院分区：
文献类型：
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作者：
Paulsson, Johan O.;Backman, Samuel;Juhlin, C. Christofer
人们对甲状腺癌去分化的遗传学研究还只有部分了解，还没有利用全面的泛基因组分析来确定其特征。我们利用全基因组测序(WGS)研究了一例罕见的同步滤泡性甲状腺癌(FTC)、低分化甲状腺癌(PDTC)和间变性甲状腺癌(ATC)，以及来自同一患者的PDTC和ATC的区域淋巴转移。FTC显示CALR、RB1和MSH2突变，PDTC显示TP53、DROSHA、APC、TERT和其他DNA修复基因突变-与亚克隆体突变的巨大增加有关。在PDTC和ATC中，所有成分都表现出过度的C&gT；T转变和相关的微卫星不稳定性(MSI)，而在FTC中，微卫星不稳定性(MSI)与之接近。克隆性分析精确地找到了一个共享的祖先克隆，该克隆丰富了与TP53相关的DNA修复调节中的突变，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。这种甲状腺癌自然发展的基因组特征揭示了几个对未来研究感兴趣的新基因。此外，这些发现支持逐步去分化过程的理论，并表明DNA修复缺陷可能在甲状腺癌的克隆进化中发挥重要作用。(C)2019年大不列颠和爱尔兰病理学会。作者：John Wiley&Sons，Ltd.
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. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.