A Tuft Cell–Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer Histotypes

Yamada, Yosuke; Simon-Keller, Katja; Belharazem-Vitacolonnna, Djeda; Bohnenberger, Hanibal; Kriegsmann, Mark; Kriegsmann, Katharina; Hamilton, Gerhard; Graeter, Thomas; Preißler, Gerhard; Ott, German; Roessner, Eric Dominic; Dahmen, Ilona; Thomas, Roman K.; Ströbel, Philipp; Marx, Alexander

doi:10.1016/j.jtho.2021.02.008

Cited by 50 publications

(100 citation statements)

References 45 publications

(93 reference statements)

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“…Since gender and WHO histotype distribution as well as GTF2I mutation rates were similar in the Indian and German cohort and in line with a previous world-wide study ( 6 ), racial-ethnic, environmental and lifestyle factors appear not to have a major impact on the molecular mechanism(s) driving the development of thymomas. A similar conclusion was recently drawn in relation to thymic squamous cell carcinomas in which age-related rather than racial-ethnic and environmental factors appear to be related to oncogenesis (6 , 21) .…”

Section: Discussionsupporting

confidence: 79%

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study

Jain

Guleria

Singh

et al. 2021

Pathol. Oncol. Res.

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Thymomas are the most frequent adult mediastinal cancers. Their etiology is unknown and their pathogenesis poorly understood. Racial, ethnic and environmental factors influence tumorigenesis in many cancers, but their role in thymomas remains unclear to date. In this study that included pretreatment thymoma cases from India and Germany (n = 37 and n = 77, respectively) we compared i) the prevalence of the thymoma-specific chromosome 7 c.74146970T > A mutation of the GTF2I gene in type A and AB thymomas; ii) epidemiological features; and iii) the frequency of myasthenia gravis (MG). Due to a known predominance of GTF2I mutation in A and AB histotypes, we included only a marginal number of type B thymomas as a control group in both cohorts. While the distribution of histological types between the cohorts was similar (p = 0.1622), Indian patients were strikingly younger (p < 0.0001; median age 50 vs. 65 years) and showed significantly lower tumour stage (Masaoka-Koga stage I) at primary diagnosis (p = 0.0005) than the German patients. In patients with known MG status (n = 17 in Indian and n = 25 in German cohort), a clear trend towards more frequent MG was observed in the Indian group (p = 0.0504; 48 vs. 82%). The prevalence of the GTF2I mutation (analysed in n = 34 Indian and n = 77 German patients) was identical in the two cohorts. We conclude that racial-ethnic and environmental factors do not significantly influence the most common molecular feature of thymomas but may have an impact on the timing of clinical presentation.

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Section: Discussionsupporting

confidence: 79%

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study

Jain

Guleria

Singh

et al. 2021

Pathol. Oncol. Res.

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“…JASPAR analysis revealed that POU2F3 carries 6 putative SOX9-binding sites along its DNA transcriptional regulatory region, with a homology higher than 80% (Supplementary Table 7). In addition, SOX9 expression was positively associated with the expressions of TRPM5, which is required for the function of thymic tuft cells, and KIT, which is frequently expressed in thymic carcinomas (Figure 3E) (25,28). Moreover, we observed that SOX9 was correlated with almost all members of the TAS2R family (Figure 4) which are overexpressed in thymic tuft cells (25).…”

Section: Sox9 Was Correlated With Genes Associated With the Thymic Tuft Cells Phenotype In Thymomamentioning

confidence: 72%

“…In thymomas, we found that SOX9 expression was positively correlated with the expression of HIPK2, which is a critical transcriptional factor determining thymic tuft cells development and shaping thymic function (25). POU2F3, which is required for the development and function of thymic tuft cells, was found to be highly expressed in thymic squamous cell carcinomas (25,28). By JASPAR analysis, we found that POU2F3 might be a target of SOX9.…”

Section: Discussionmentioning

confidence: 87%

“…In addition, the GO enrichment analysis revealed that these 63 genes were involved in extracellular matrix organization and sensory organ morphogenesis (Figure 3D and Supplementary Table 6). Among these genes, POU2F3, a transcriptional factor for thymic tuft cells development (25,28), was shown to be positively correlated with SOX9 expression (Figure 3E, P <0.001, R 2 = 0.445). JASPAR analysis revealed that POU2F3 carries 6 putative SOX9-binding sites along its DNA transcriptional regulatory region, with a homology higher than 80% (Supplementary Table 7).…”

Section: Sox9 Was Correlated With Genes Associated With the Thymic Tuft Cells Phenotype In Thymomamentioning

confidence: 96%

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Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor

et al. 2021

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BackgroundThymic epithelial tumors (TETs) are rare tumors originating from the thymic epithelial cells. SOX9, a member of the family of SOX (SRY-related high-mobility group box) genes, has been considered as an oncogene and therapeutic target in various cancers. However, its role in TETs remains uncertain.MethodsUsing the immunohistochemistry method, the expression of SOX9 was analyzed in TETs tissues, including 34 thymoma (8 cases with type A, 6 with type AB, 6 with type B1, 9 with type B2, and 5 with type B3 thymomas) and 20 thymic cancer tissues and the clinicopathologic and prognostic significances were evaluated. Further bioinformatics analysis of gene expression profiles of thymomas with high and low SOX9 expressions and the corresponding survival analyses were based on the thymoma cases identified in The Cancer Genome Atlas (TCGA) database, with the median expression level of SOX9 selected as cutoff.ResultsImmunohistochemistry staining showed that SOX9 was highly expressed in the nuclei of the epithelial cells of the Hassall’s corpuscles and of the TET tumor cells. SOX9 expression was significantly associated with histological type and high expression indicated unfavorable clinical outcomes of thymomas. Bioinformatics analysis revealed that genes positively associated with SOX9 expression were mapped in proteoglycans in cancer, cell adhesion molecules, and molecules involved in extracellular matrix-receptor interaction and the TGF-β signaling pathway, and that genes negatively associated with SOX9 expression were mapped in molecules involved in primary immunodeficiency, the T cell receptor signaling pathway, Th17 cell differentiation, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. In addition, SOX9 expression was positively associated with POU2F3 and TRPM5 expressions, the master regulators of tuft cells, suggesting that high SOX9 expression might be associated with the tuft cell phenotype of thymomas. Moreover, high SOX9 expression was associated with immune dysregulation of thymoma, and M2 macrophage significantly dominated in the high SOX9 expression group.ConclusionSOX9 may serve as a diagnostic and prognostic marker for TETs. Notably, high SOX9 expression in TETs may indicate a tuft cell phenotype and an immune suppressive microenvironment of thymomas.

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“…In the thymus, tuft cells help shape the microenvironment and influence innate immunity [48][49][50]. Molecular analysis using public databases and frozen tissues revealed that POU2F3 and GFI1B, both tuft cell-related genes, are highly expressed in thymic squamous cell carcinoma [51]. In addition, the authors assessed the KIT expression status; POU2F3 expression was strongly correlated with KIT expression, suggesting that POU2F3 may drive KIT expression.…”

Section: The Biology Of Thymic Carcinomamentioning

confidence: 99%

Future Perspective of Chemotherapy and Pharmacotherapy in Thymic Carcinoma

Kitadai

Okuma

2021

Cancers

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Thymic carcinoma is a rare cancer that arises from thymic epithelial cells. Its nature and pathology differ from that of benign thymoma, presenting a poorer prognosis. If surgically resectable, surgery alone or surgery followed by chemoradiotherapy or radiotherapy is recommended by the National Comprehensive Cancer Network Guidelines. Metastatic and refractory thymic carcinomas require systemic pharmacotherapy. Combined carboplatin and paclitaxel, and cisplatin and anthracycline-based regimens have been shown a fair response rate and survival to provide a de facto standard of care when compared with other drugs employed as first-line chemotherapy. Cytotoxic agents have been pivotal for treating thymic carcinoma, as little is known regarding its tumorigenesis. In addition, genetic alterations, including driver mutations, which play an important role in treatments, have not yet been discovered. However, molecular pathways and biomarker studies assessing thymic epithelial tumors have been reported recently, resulting in the development of new agents, such as molecular targeted agents and immune checkpoint inhibitors. As treatment options are currently limited and the prognosis remains poor in metastases and recurrent thymic carcinoma, genetic alterations need to be assessed. In the present review, we focused on the current role of targeted therapies and immune checkpoint inhibitors in treating thymic carcinoma.

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A Tuft Cell–Like Signature Is Highly Prevalent in Thymic Squamous Cell Carcinoma and Delineates New Molecular Subsets Among the Major Lung Cancer Histotypes

Cited by 50 publications

References 45 publications

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study

GTF2I Mutation in Thymomas: Independence From Racial-Ethnic Backgrounds. An Indian/German Comparative Study

Diagnostic and Prognostic Significances of SOX9 in Thymic Epithelial Tumor

Future Perspective of Chemotherapy and Pharmacotherapy in Thymic Carcinoma

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