Identification of Molecular Characteristics and New Prognostic Targets for Thymoma by Multiomics Analysis

Abstract

Background. Thymoma is a heterogeneous tumor originated from thymic epithelial cells. The molecular mechanism of thymoma remains unclear. Methods. The expression profile, methylation, and mutation data of thymoma were obtained from TCGA database. The coexpression network was constructed using the variance of gene expression through WGCNA. Enrichment analysis using clusterProfiler R package and overall survival (OS) analysis by Kaplan-Meier method were carried out for the intersection of differential expression genes (DEGs) screened by limma R package and important module genes. PPI network was constructed based on STRING database for genes with significant impact on survival. The impact of key genes on the prognosis of thymoma was evaluated by ROC curve and Cox regression model. Finally, the immune cell infiltration, methylation modification, and gene mutation were calculated. Results. We obtained eleven coexpression modules, and three of them were higher positively correlated with thymoma. DEGs in these three modules mainly involved in MAPK cascade and PPAR pathway. LIPE, MYH6, ACTG2, KLF4, SULT4A1, and TF were identified as key genes through the PPI network. AUC values of LIPE were the highest. Cox regression analysis showed that low expression of LIPE was a prognostic risk factor for thymoma. In addition, there was a high correlation between LIPE and T cells. Importantly, the expression of LIPE was modified by methylation. Among all the mutated genes, GTF2I had the highest mutation frequency. Conclusion. These results suggested that the molecular mechanism of thymoma may be related to immune inflammation. LIPE may be the key genes affecting prognosis of thymoma. Our findings will help to elucidate the pathogenesis and therapeutic targets of thymoma.

Molecular profiling of rare thymoma using next-generation sequencing: meta-analysis

“…TCGA’s studies of thymoma have shown recurrent mutations in the GTF2I gene and suggested this gene as a potential drug target for this disease. 23 , 24 , 25 Our findings confirm the prevalence of the SNVs/InDels variants in GTF2I in thymoma. Results have been reported in several articles which have been presented in the Forest and Funnel plots.…”

Non-Mutational Key Features in the Biology of Thymomas

“…Many studies have analyzed mRNA expression profiles in TETs [ 4 , 13 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 ]. However, the results are difficult to compare due to differences in the study focus, methodology, number of samples, controls (e.g., TH vs. normal thymus, TH vs. TC, TH with and without myasthenia gravis).…”

“…THs with GTF2I mutations (type A and AB thymomas) were enriched for genes related to human embryonic stem cell pluripotency and Wnt/β-catenin signaling [ 82 ], lymphocyte-rich type B1 and B2 thymomas were enriched for genes related to T-cell receptor signaling, CTLA4 signaling, and ICOS/ICOSL signaling, whereas type B3 thymomas overexpressed genes related to G protein-coupled receptor signaling, Toll-like receptor signaling regulation of epithelial–mesenchymal transition (EMT) as well as NF-κB, EGF, FAK, and telomerase signaling. Differentially regulated pathways that were identified in more than one study included cell cycle regulation [ 4 , 72 , 79 , 81 ], MAPK/ERK signaling [ 4 , 78 ], hormone signaling [ 4 , 72 ], Wnt signaling [ 78 , 82 ], and apoptosis [ 4 , 81 ]. In a study by Badve et al, the top pathways associated with metastasis were amino acid metabolism, steroid and glycosphingolipid biosynthesis, cell cycle checkpoint proteins, and Notch signaling [ 72 ].…”

Thymoma: An Overview

“…In the past decade, many investigations have been conducted in an effort to characterize the molecular profile of thymic epithelial neoplasms, including thymoma. Thymomas typically have low mutational burdens and a variety of copy number abnormalities [ 44 , 45 ] (summarized in Table 2 ). The observed low mutation burden in thymomas has been associated with the smaller number of somatic mutations present in the DNA of neoplastic cells [ 46 ].…”

“…The most common molecular alteration in thymoma type A, type AB, type B2, and type B3 is the loss of heterozygosity across chromosome 6 (the 6q25.2-p25.3 region contains the FOXC1 tumor suppressor gene) [ 45 , 47 ]. This particular alteration was not detected in thymoma type B1.…”