Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Department of Human Genetics, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan.
Endocrine. 2019 Dec;66(3):607-613. doi: 10.1007/s12020-019-02063-z. Epub 2019 Sep 2.
Papillary thyroid cancers (PTCs) are the most common type of thyroid cancers, in which BRAF is the most prevalent driver mutation. It is known that BRAF-positive PTCs are clinically and molecularly heterogenous in terms of aggressiveness and prognosis. The molecular mechanisms of this heterogeneity were evaluated.
The publicly available RNA-seq data for 26 classical (c) and 5 follicular variant (fv) PTCs with BRAF mutation and the BRAF-like expression signature in the BRAF-RAS score (BRS) and their respective normal adjacent tissues were downloaded, and analyzed for differentially expressed genes (DEGs). The DEGs were then analyzed with the Gene Ontology annotation and the KEGG pathway dataset.
We found four lines of evidence for heterogeneity of cPTCs. First, the cluster dendrogram and principle component analyses could not completely distinguish the cancer tissues from normal tissues. Second, the DEGs identified in each sample were highly diverse from one another. Third, although the DEGs were enriched in many terms containing the word "extracellular" ("extracellular region", "extracellular space", and so on) when analyzed as groups, the degree of this enrichment was variable when analyzed individually. Fourth, there are only a few intersections in the over-/underexpressed genes annotated with the terms containing the word "extracellular" among the samples examined. Essentially same results were obtained with BRAF-like, fvPTCs with BRAF. Nevertheless, some frequently over-/underexpressed genes were detected, of which LIPH (lipase H) expression was found to be prognostic and its high expression was favorable for PTCs.
Groups of BRAF-like, BRAF-positive cPTCs and fvPTCs that are homogenous in regard to histopathology, driver mutation and BRS were found to be highly heterogenous in terms of gene expression patterns. Yet, among the genes that were annotated with the terms containing the word "extracellular" and frequently over-/underexpressed, LIPH is a favorable prognostic marker for PTCs.
甲状腺癌（PTC）是最常见的甲状腺癌类型，其中 BRAF 是最常见的驱动突变。已知 BRAF 阳性 PTC 在侵袭性和预后方面具有临床和分子异质性。评估了这种异质性的分子机制。
下载了 26 例经典型（c）和 5 例滤泡变体（fv）PTC 中具有 BRAF 突变的 BRAF 阳性 PTC 及其各自的正常相邻组织的公开可用的 RNA-seq 数据，并分析了差异表达基因（DEGs）。然后使用基因本体论注释和 KEGG 途径数据集对 DEGs 进行了分析。
我们发现 cPTC 存在四条异质性的证据。首先，聚类树状图和主成分分析不能完全区分癌症组织和正常组织。其次，每个样本中鉴定的 DEGs 彼此之间差异很大。第三，尽管当作为组进行分析时，鉴定的 DEGs 在许多包含“细胞外”一词的术语中富集（“细胞外区域”、“细胞外空间”等），但当单独分析时，这种富集的程度是可变的。第四，在被包含“细胞外”一词的术语注释的过/低表达基因中，检查的样本之间只有很少的交集。用 BRAF 样、BRAF 阳性 fvPTC 进行同样的分析也得到了基本相同的结果。然而，检测到一些经常过/低表达的基因，其中 LIPH（脂肪酶 H）的表达被发现具有预后意义，其高表达对 PTC 有利。
在组织病理学、驱动突变和 BRS 方面同质的 BRAF 样、BRAF 阳性 cPTC 和 fvPTC 组在基因表达模式方面表现出高度异质性。然而，在被包含“细胞外”一词的术语注释且经常过/低表达的基因中，LIPH 是 PTC 的有利预后标志物。
