PDF(Pubmed)
Abstract：
BACKGROUND: Primary squamous cell carcinoma (SCC) of the thyroid and anaplastic thyroid carcinoma (ATC) show significant clinical and histologic overlap. Their biological behaviors are so similar that the fifth WHO updates SCC as a morphologic pattern of ATC rather than a separate entity. However, molecular genomic evidence that determines them as the same histologic type is limited. We aimed to explore whether they belong to the same classification from a molecular-typing perspective.
METHODS: A cohort enrolled 15 SCCs and 15 ATCs was collected. Whole exome sequencing (WES) and RNA-sequencing were performed to analyze molecular genetic and gene-expression profiles.
RESULTS: Significantly differential-mutant genes were BRAF, DPCR1, PCYOX1L, BRSK2, NRG1, PRR14L, TET1, VAMP4 suggesting differences in mutation level, as well as differences in high-frequency mutated genes, and SCC had a much lower tumor mutation burden than ATC. Mutational co-occurrence and mutual exclusion were less frequent in SCC than in ATC. 2047 differential-express genes were screened, indicating differences in gene expression were extremely strong. In principal component analysis, ATC and SCC could be notably clustered together, respectively, meanwhile they could be explicitly distinguished. Unsupervised clustering analysis validated they can indeed be clearly separated from each other which demonstrated that they may be two distinctive entities.
CONCLUSIONS: It is controversial yet SCC is classified as a morphologic pattern of ATC. We revealed that SCC exhibited molecular genetic characteristics distinct from ATC. Although the fifth WHO categorizes them together, this study may provide strong molecular genetic evidence for the next edition of WHO classification that may allow for the separation of thyroid SCC from ATC.
METHODS: A cohort enrolled 15 SCCs and 15 ATCs was collected. Whole exome sequencing (WES) and RNA-sequencing were performed to analyze molecular genetic and gene-expression profiles.
RESULTS: Significantly differential-mutant genes were BRAF, DPCR1, PCYOX1L, BRSK2, NRG1, PRR14L, TET1, VAMP4 suggesting differences in mutation level, as well as differences in high-frequency mutated genes, and SCC had a much lower tumor mutation burden than ATC. Mutational co-occurrence and mutual exclusion were less frequent in SCC than in ATC. 2047 differential-express genes were screened, indicating differences in gene expression were extremely strong. In principal component analysis, ATC and SCC could be notably clustered together, respectively, meanwhile they could be explicitly distinguished. Unsupervised clustering analysis validated they can indeed be clearly separated from each other which demonstrated that they may be two distinctive entities.
CONCLUSIONS: It is controversial yet SCC is classified as a morphologic pattern of ATC. We revealed that SCC exhibited molecular genetic characteristics distinct from ATC. Although the fifth WHO categorizes them together, this study may provide strong molecular genetic evidence for the next edition of WHO classification that may allow for the separation of thyroid SCC from ATC.
摘要：
背景：原发性甲状腺鳞状细胞癌（SCC）和未分化甲状腺癌（ATC）显示出明显的临床和组织学重叠。它们的生物学行为非常相似，以至于第五届WHO将SCC更新为ATC的形态模式，而不是单独的实体。然而,确定它们为相同组织学类型的分子基因组证据是有限的。我们旨在从分子分型的角度探讨它们是否属于同一分类。
方法：一个队列纳入了15个SCCs和15个ATC。进行全外显子组测序(WES)和RNA测序以分析分子遗传和基因表达谱。
结果：显著差异突变基因为BRAF，DPCR1,PCYOX1L,BRSK2,NRG1,PRR14L,TET1，VAMP4表明突变水平的差异，以及高频突变基因的差异，SCC的肿瘤突变负荷远低于ATC。SCC中的突变共现和相互排斥的频率低于ATC。筛选了2047个差异表达基因，表明基因表达差异极强。在主成分分析中，ATC和SCC可以明显地聚集在一起，分别,同时，它们可以明确区分。无监督聚类分析验证了它们确实可以彼此清楚地分离，这表明它们可能是两个不同的实体。
结论：尽管SCC被归类为ATC的一种形态模式，但仍存在争议。我们发现SCC表现出与ATC不同的分子遗传特征。尽管第五世界卫生组织将它们分类在一起，这项研究可能为下一版WHO分类提供强有力的分子遗传学证据,该分类可能允许分离甲状腺SCC和ATC.
方法：一个队列纳入了15个SCCs和15个ATC。进行全外显子组测序(WES)和RNA测序以分析分子遗传和基因表达谱。
结果：显著差异突变基因为BRAF，DPCR1,PCYOX1L,BRSK2,NRG1,PRR14L,TET1，VAMP4表明突变水平的差异，以及高频突变基因的差异，SCC的肿瘤突变负荷远低于ATC。SCC中的突变共现和相互排斥的频率低于ATC。筛选了2047个差异表达基因，表明基因表达差异极强。在主成分分析中，ATC和SCC可以明显地聚集在一起，分别,同时，它们可以明确区分。无监督聚类分析验证了它们确实可以彼此清楚地分离，这表明它们可能是两个不同的实体。
结论：尽管SCC被归类为ATC的一种形态模式，但仍存在争议。我们发现SCC表现出与ATC不同的分子遗传特征。尽管第五世界卫生组织将它们分类在一起，这项研究可能为下一版WHO分类提供强有力的分子遗传学证据,该分类可能允许分离甲状腺SCC和ATC.
