Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes

Yamada, Yosuke; Weis, Cleo–Aron; Thelen, Julian; Sticht, Carsten; Schalke, Berthold; Ströbel, Philipp; Marx, Alexander

doi:10.3389/fimmu.2020.00664

Cited by 27 publications

(28 citation statements)

References 31 publications

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“…It is the high frequency of ICIinduced severe immune-mediated toxicity that currently prohibits adoption of immunotherapy, including ICIs for the management of thymomas. 15 Whether aneuploidy and particular transcriptomic profiles that were found to be associated with the presence of autoimmune myasthenia gravis in thymomas 7,25 may serve as predictive biomarkers of immune-mediated adverse events associated with ICIbased interventions has not been evaluated.…”

Section: Features Maintainedmentioning

confidence: 99%

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

Marx

Chan

Chalabreysse³

et al. 2022

Journal of Thoracic Oncology

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This overview of the fifth edition of the WHO classification of thymic epithelial tumors (including thymomas, thymic carcinomas, and thymic neuroendocrine tumors [NETs]), mediastinal germ cell tumors, and mesenchymal neoplasms aims to (1) list established and new tumor entities and subtypes and (2) focus on diagnostic, molecular, and conceptual advances since publication of the fourth edition in 2015. Diagnostic advances are best exemplified by the immunohistochemical characterization of adenocarcinomas and the recognition of genetic translocations in metaplastic thymomas, rare B2 and B3 thymomas, and hyalinizing clear cell carcinomas. Advancements at the molecular and tumor biological levels of utmost oncological relevance are the findings that thymomas and most thymic carcinomas lack currently targetable mutations, have an extraordinarily low tumor mutational burden, but typically have a programmed death-ligand 1 high phenotype. Finally, data underpinning a conceptual advance are illustrated for the future classification of thymic NETs that may fit into the classification scheme of extrathoracic NETs. Endowed with updated clinical information and state-of-the-art positron emission tomography and computed tomography images, the fifth edition of the WHO classification of thymic epithelial tumors, germ cell tumors, and mesenchymal neoplasms with its wealth of new diagnostic and molecular insights will be a valuable source for pathologists, radiologists, surgeons, and oncologists alike. Therapeutic perspectives and research challenges will be addressed as well.

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Section: Features Maintainedmentioning

confidence: 99%

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

Marx

Chan

Chalabreysse³

et al. 2022

Journal of Thoracic Oncology

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163

172

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“…However, the neuropeptide is only one of the ways that the nervous system regulates the immune system, and whether other neuroregulatory mechanisms were involved in the development of MG requires further exploration. Notably, a research from Yamada et al ( 33 ) has shown that the pathogenesis of TAMG might be quite different between the different thymoma histotypes. Therefore, further studies focusing on the pathogenesis of TAMG should consider the histotypes of thymoma.…”

Section: Discussionmentioning

confidence: 99%

“…In has been explored that the pathology of tumor vessel is quite different between different thymoma subtypes ( 44 ). However, the tumor vasculature in TAMG is merely discussed ( 33 ). In this study, we found that the LINC00452/miR-204/CHST4 axis may regulate Treg cells in the progression of MG. CHST4 is expressed specifically in the high endothelial venule (HEV) ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

The LINC00452/miR-204/CHST4 Axis Regulating Thymic Tregs Might Be Involved in the Progression of Thymoma-Associated Myasthenia Gravis

et al. 2022

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BackgroundMyasthenia gravis (MG) is an autoimmune disease that mainly affects neuromuscular junctions and is usually associated with immune disorders in the thymoma. The competitive endogenous RNA (ceRNA) hypothesis has been demonstrated to be an intrinsic mechanism regulating the development of several autoimmune diseases; however, the mechanism where the ceRNA network regulates immune cells in patients with thymoma-associated MG (TAMG) has rarely been explored.MethodsRNA-seq data and clinical information of 124 patients with thymoma were obtained from The Cancer Genome Atlas (TCGA) database. The patients were divided into two groups according to whether they were diagnosed with MG. We applied the propensity score matching method to reduce the incidence of baseline confounders. We then constructed a ceRNA network with differentially expressed RNAs between the groups based on four public databases. The expression of genes of interest was validated by qPCR. Moreover, we predicted the immune cells that infiltrated the thymoma and then analyzed the association between immune cells and RNA in the ceRNA network. To further determine the function of the mRNAs associated with immune cells in patients with TAMG, we performed gene set enrichment analysis in thymoma patients with MG.ResultsAfter matching, 94 patients were included in the following analysis. A total of 847 mRNAs, 409 lncRNAs, and 45 miRNAs were differentially expressed between the groups. The ceRNA network, including 18 lncRNAs, four miRNAs, and 13 mRNAs, was then constructed. We then confirmed that CHST4 and LINC00452, miR-204-3p and miR-204-5p were differentially expressed between patients with TAMG and thymoma patients without MG (NMG) by qPCR. Moreover, we found that the percentage of predicted regulatory T (Treg) cells was significantly decreased in patients with TAMG. Further analysis indicated that the LINC00452/miR-204/CHST4 axis might regulate thymic regulatory T cells (Tregs) in the progression of MG.ConclusionsIn this research, we constructed a ceRNA network involved in the progression of TAMG, discovered that thymic Tregs were significantly decreased in patients with TAMG, and assumed that the LINC00452/miR-204/CHST4 axis may regulate thymic Tregs in the development of TAMG. These findings may deepen our understanding of the roles of the ceRNA network in regulating TAMG and highlight the function of CHST4 in recruiting peripheral T cells in the progression of TAMG.

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“…GO and KEGG analysis revealed that the target genes of the immune-related We identified three immune-related lncRNAs (AC004943.1, WT1-AS and FOXG1-AS1) which were alter in methylation and expression, and found the target genes of these immunrelated lncRNAs were enriched in "regulated transcription coregulator activity", "cell cycle", "actin binding", "axon guidance", "Ras GTPase binding" and "herpes simplex virus 1 infection". Previous study explored the functional pathways of thymoma and thymoma-related MG have found that differential expression of functional pathways were associated to MG in different thymoma histotypes (Yamada et al, 2020). Another recent study focus on the genetic characterization of thymoma found some signal pathways that enriched by the upregulated genes in thymoma with MG may be responsible for MG in thymoma patients (Yu, Ke, Du, Yu, & Gao, 2019).…”

Section: Discussionmentioning

confidence: 99%

Immune-Related Molecular Profiling of Thymoma With Myasthenia Gravis

et al. 2021

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Background: Approximately 50% of thymoma patients also show myasthenia gravis (MG), which is an autoimmune disease; however, the pathogenesis of MG-associated thymoma remains elusive. Our aim was to investigate immune-related lncRNA profiles of a set of candidate genes for better understanding of the molecular mechanism underlying the pathogenesis of thymoma with or without MG.Methods: Molecular profiles of thymoma with or without MG were downloaded from The Cancer Genome Atlas, and Pearson’s correlation analysis was performed to identify immune-related lncRNAs. T test was used to examine the differential expression and differential methylation between thymoma patients with or without MG. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed to predict the function of target genes of immune-related lncRNAs.Results: Analyses of the 87 thymoma samples with complete MG information revealed that 205 mRNAs and 56 lncRNAs showed up-regulated expression in thymoma with MG patients, while 458 mRNAs and 84 lncRNAs showed down-regulated expression. The methylation level of three immune-related lncRNAs (AP000787.1, AC004943.1, WT1-AS, FOXG1-AS1) was significantly decreased in thymoma tissues, and the methylation level of these immune-related lncRNAs (WT1-AS: Cor = 0.368, p < 0.001; FOXG1-AS1: Cor = 0.288, p < 0.01; AC004943.1: Cor = -0.236, p < 0.05) correlated with their expression. GO and KEGG pathway analysis revealed that targets of the immune-related lncRNA FOXG1-AS1 were enriched in small GTPase binding and herpes simplex virus 1 infection. Transcription coregulator activity and cell cycle were the most enriched pathways for targets of lncRNA AC004943.1. LncRNA WT1-AS targets were most enriched in actin binding and axon guidance.Conclusion: Our results revealed the immune-related molecular profiling of thymoma with MG and without MG and identified key pathways involved in the underlying molecular mechanism of thymoma-related MG. These findings provide insights for further research of potential markers for thymoma-related MG.

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Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes

Cited by 27 publications

References 31 publications

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

The 2021 WHO Classification of Tumors of the Thymus and Mediastinum: What Is New in Thymic Epithelial, Germ Cell, and Mesenchymal Tumors?

The LINC00452/miR-204/CHST4 Axis Regulating Thymic Tregs Might Be Involved in the Progression of Thymoma-Associated Myasthenia Gravis

Immune-Related Molecular Profiling of Thymoma With Myasthenia Gravis

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