胸腺瘤的遗传学特征。
Genetic characterization of thymoma.
机构信息
Department of Thoracic Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China.
出版信息
Sci Rep. 2019 Feb 20;9(1):2369. doi: 10.1038/s41598-019-38878-z.
Thymoma represents the most common anterior mediastinal compartment neoplasm, originating from the epithelial cell population in the thymus. Various histological types of thymoma feature different clinical characteristics. Furthermore, thymoma is frequently associated with autoimmune disorders, esp. myasthenia gravis (MG). However, the underlying molecular tumourigenesis of thymoma remains largely unknown. The goal of our current study is to demonstrate the underlying genetic abberations in thymoma, so as to understand the possible cause of MG in thymoma patients. By using CapitalBio mRNA microarray analysis, we analyzed 31 cases of thymoma including 5 cases of type AB thymoma, 6 B1-type cases, 12 B2-type cases, 5 B2B3-type cases and 3 type-B3 cases. 6 cases of thymoma were not associated with myasthenia gravis, while 25 cases were with myasthenia gravis. By comparisons between thymoma and the paratumoral tissues, differentially expressed genes were identified preliminarily. Among them, 292 genes increased more than 2-fold, 2 genes more than 5-fold. On the other hand, 596 genes were decreased more than 2-fold, 6 genes more than 20-fold. Interestingly, among these genes upregulated more than 2-fold, 6 driver genes (FANCI, NCAPD3, NCAPG, OXCT1, EPHA1 and MCM2) were formerly reported as driver oncogenes. This microarray results were further confirmed through real-time PCR. 8 most dysregulated genes were verified: E2F2, EPHA1, CCL25 and MCM2 were upregulated; and IL6, FABP4, CD36 and MYOC were downregulated. Supervised clustering heat map analysis of 2-fold upregulated and 2-fold downregulated genes revealed 6 distinct clusters. Strikingly, we found that cluster 1 was composed of two type-B2 thymoma; and cluster 6 was three type-B2/B3 thymoma. KEGG database analysis revealed possible genetic mechanisms of thymoma and functional process. We further compared gene expression pattern between thymoma with and without MG, and found 5 genes were upregulated more than 2-fold, more than 30 genes were downregulated more than 2-fold. KEGG analysis revealed 2 important signaling pathways with more than 2-fold upregulated genes (TGF- beta signaling pathway and HTLV-I signaling pathway) as differially functioning between MG positive and negative thymomas. Real-time PCR analysis confirmed that CCL25 was upregulated; and MYC, GADD45B, TNFRSF12 downregulated in thymoma with MG. Our study thus provided important genetic information on thymoma. It shed light on the molecular bases for analyzing the functional process of thymoma and finding potential biomarkers for pathological categorizing and treatment. Our work may provide important clues in understanding possible causes of MG in thymoma patients.
胸腺瘤是最常见的前纵隔腔肿瘤，源自胸腺上皮细胞群。各种组织类型的胸腺瘤具有不同的临床特征。此外，胸腺瘤常与自身免疫性疾病相关，特别是重症肌无力（MG）。然而，胸腺瘤的潜在分子肿瘤发生机制在很大程度上仍是未知的。我们目前的研究旨在展示胸腺瘤的潜在遗传异常，以了解胸腺瘤患者发生 MG 的可能原因。通过使用 CapitalBio mRNA 微阵列分析，我们分析了 31 例胸腺瘤，包括 5 例 AB 型胸腺瘤、6 例 B1 型、12 例 B2 型、5 例 B2B3 型和 3 例 B3 型。6 例胸腺瘤与重症肌无力无关，而 25 例胸腺瘤与重症肌无力有关。通过比较胸腺瘤与肿瘤旁组织，初步确定了差异表达的基因。其中，292 个基因表达增加了 2 倍以上，2 个基因表达增加了 5 倍以上。另一方面，596 个基因表达减少了 2 倍以上，6 个基因表达减少了 20 倍以上。有趣的是，在这些表达增加 2 倍以上的基因中，6 个驱动基因（FANCI、NCAPD3、NCAPG、OXCT1、EPHAl 和 MCM2）以前被报道为驱动癌基因。这些微阵列结果通过实时 PCR 进一步得到证实。对 8 个最失调的基因进行了验证：E2F2、EPHAl、CCL25 和 MCM2 表达上调；而 IL6、FABP4、CD36 和 MYOC 表达下调。2 倍上调和 2 倍下调基因的监督聚类热图分析显示了 6 个不同的簇。引人注目的是，我们发现簇 1 由两个 B2 型胸腺瘤组成；簇 6 由三个 B2/B3 型胸腺瘤组成。KEGG 数据库分析揭示了胸腺瘤的可能遗传机制和功能过程。我们进一步比较了有和无 MG 的胸腺瘤之间的基因表达模式，发现有 5 个基因表达增加了 2 倍以上，有 30 个基因表达减少了 2 倍以上。KEGG 分析显示，有 2 个重要的信号通路（TGF-β信号通路和 HTLV-I 信号通路）的基因表达增加了 2 倍以上，这是 MG 阳性和阴性胸腺瘤之间差异表达的通路。实时 PCR 分析证实 CCL25 表达上调；而 MYC、GADD45B、TNFRSF12 在伴有 MG 的胸腺瘤中表达下调。因此，我们的研究提供了胸腺瘤的重要遗传信息。它为分析胸腺瘤的功能过程以及寻找潜在的病理分类和治疗标志物提供了分子基础。我们的工作可能为理解胸腺瘤患者发生 MG 的可能原因提供了重要线索。
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