METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors

Abstract Background Thymic epithelial tumors (TETs) are rare neoplasms, originating from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined, and a deeper molecular characterization could result in a relevant advance in their management, greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in cell differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype and favors migration and invasiveness, but its role in Thymic Tumors remains unknown. Results In this study, we characterized that METTL3 contributes to Thymic Epithelial Tumor phenotype. We evidenced that METTL3 is overexpressed in tumor tissue compared to normal counterpart. Silencing of METTL3 expression in thymic carcinoma cells results in reduced cell proliferation and overall translation rate. Of note, METTL3 is responsible for the induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Interestingly, blocking of c-MYC by using JQ1 inhibitor cooperates with METTL3 depletion in the inhibition of proliferation and induction of cell death. Conclusion This study highlighted METTL3 as a tumor promoter in Thymic tumors and c-MYC as a promising target to be exploited for the treatment of TET.

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Synchronous Double Thymic Tumors (a Typical Carcinoid and Combined Thymic Epithelial Tumors) and Triple Lung Adenocarcinomas: Report of a Case

Haigan ◽

10.2482/haigan.53.154 ◽

2013 ◽

Vol 53 (2) ◽

pp. 154-158

Author(s):

Tetsuya Yokosuka ◽

Toshiko Kobayashi

Keyword(s):

Typical Carcinoid ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Lung Adenocarcinomas ◽

Thymic Tumors

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Oncological resection, myasthenia gravis and staging as prognostic factors in thymic tumors: A Chilean case series

10.21203/rs.2.24269/v1 ◽

2020 ◽

Author(s):

Patricio Salas ◽

Maria Eliana Solovera ◽

Felipe Bannura ◽

Matias Muñoz-Medel ◽

Miguel Cordova-Delgado ◽

...

Keyword(s):

Prognostic Factors ◽

Myasthenia Gravis ◽

Staging System ◽

The United States ◽

Study Patient ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Quality Of Surgery ◽

Staging Systems ◽

Thymic Tumors

Abstract Background: Thymic epithelial tumors are rare and highly heterogeneous. Reports from the United States suggest an overall incidence of 0.15 per 100,000/year. In contrast, the incidence of these tumors in Latin America is largely unknown and reports are scarce, somewhat limited to case reports.Methods: Herein, we report a series of 38 thymic tumors from a single institution, retrospectively incorporated into this study. Patient characteristics and outcomes including age, sex, stage, paraneoplastic syndromes, treatment regimens and the date of decease were obtained from medical records.Results: Most cases in our series were females and young age (<50 years-old) and early stage by Masaoka-Koga or the Moran staging systems. Also, a 34% of patients had myasthenia gravis (MG). Next, we analyzed overall survival (OS) rates in our series and found that the quality of surgery (R0, R1 or R2), MG status, and staging (Masaoka-Koga or Moran) were prognostic factors. Finally, we compared our data to larger thymic tumor series.Conclusions: Overall, our study confirms complete surgical resection as the standard, most effective treatment for thymic epithelial tumors. Also, the Masaoka-Koga staging system remains as a reliable prognostic factor but also the Moran staging system should be considered for thymomas.

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Extracellular volume fraction measurement correlates with lymphocyte abundance in thymic epithelial tumors

Cancer Imaging ◽

10.1186/s40644-020-00349-4 ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Chao-Chun Chang ◽

Chia-Ying Lin ◽

Chang-Yao Chu ◽

Yi-Cheng Hsiung ◽

Ming-Tsung Chuang ◽

...

Keyword(s):

T1 Mapping ◽

Thymic Carcinoma ◽

Volume Fraction ◽

Extracellular Volume ◽

Quantitative Mri ◽

Low Grade ◽

Epithelial Tumor ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Thymic Epithelial Tumor

Abstract Background Recent advance in tissue characterization with parametric mapping imaging has the potential to be a novel biomarker for histopathologic correlation with thymic epithelial tumors (TETs). The purpose of our study is to evaluate MRI T1 mapping with the calculation of extracellular volume (ECV) fraction for histologic correlation with thymic epithelial tumor based on lymphocyte abundance. Methods A retrospective study including 31 consecutive patients (14 men and 17 women, median age, 56 years; interquartile range, 12 years) with TETs was performed. The T1 values and ECV were assessed by using quantitative MRI mapping techniques. Mann-Whitney U test, Kruskal-Wallis H test, and receiver operating characteristic curve analyses were used to assess discrimination between different types of TETs based on lymphocyte abundance. Results Extracellular volume was significantly higher in TETs with sparse lymphocyte, including type A, type B3, and thymic carcinoma, compared with those with abundant lymphocyte, including type B1, B2, and AB thymomas (42.5% vs 26.9%, respectively; p < 0.001). Extracellular volume was significantly higher in thymic carcinoma compared with low grade and high grade thymomas (48.6% vs 31.1% vs 27.6%, respectively; p = 0.002). Conclusions T1 mapping with the calculation of extracellular volume (ECV) fraction correlate with the WHO histologic classification of thymic epithelial tumor based on lymphocyte abundance.

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Clinical outcome of patients with thymic epithelial tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.14148 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 14148-14148

Author(s):

G. Palmieri ◽

L. Montella ◽

G. Merola ◽

C. Merola ◽

E. Matano ◽

...

Keyword(s):

Clinical Status ◽

Patient Characteristics ◽

Clinical Activity ◽

Preliminary Evaluation ◽

Treatment Schedule ◽

Epithelial Tumor ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Egfr Expression ◽

Therapeutic Choice

14148 Advanced chemorefractory thymic epithelial tumors still represent a challenge in clinical oncology. Neoplastic thymoma cells express EGFR. We evaluated the clinical activity of Cetuximab, a chimeric human-mouse monoclonal IgG1 antibody blocking ligand binding to EGFR, in five cases of advanced chemorefractory thymic epithelial tumor. Materials and Methods: Patient Characteristics and response evaluation. Patients’ characteristics and responses to treatment are represented in the table . The patients were assessed for EGFR expression in the primitive tumor, being considered this data as a basis for an anti EGFR treatment. Moreover they were evaluated as concerns clinical status and biochemistry and imaged by a combined PET-CT. Treatment schedule: The patients received intravenous cetuximab (C225, Erbitux, Merck KgaA, Darmstadt, Germany) over 1 hour at 400 mg/m2 loading dose followed by the weekly administration of 250 mg/m2. The first dose of 400 mg/m2 was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m2 during the course of 1 hour. This preliminary evaluation suggests for the first time that cetuximab may be a useful therapeutic choice in advanced pretreated thymic tumors. Despite the need for prolonged follow-up of the patients and further confirmatory studies, the EGF/EGFR pathway seems to play a pivotal role in thymic tumor. [Table: see text] No significant financial relationships to disclose.

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The tumor doubling time is a useful parameter for predicting the histological type of thymic epithelial tumors

Surgery Today ◽

10.1007/s00595-019-01822-9 ◽

2019 ◽

Vol 49 (8) ◽

pp. 656-660 ◽

Cited By ~ 1

Author(s):

Koichi Fukumoto ◽

Takayuki Fukui ◽

Koji Kawaguchi ◽

Shota Nakamura ◽

Shuhei Hakiri ◽

...

Keyword(s):

Doubling Time ◽

Histological Type ◽

Tumor Doubling Time ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors

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Prognostic Significance of Metabolic Parameters by 18F-FDG PET/CT in Thymic Epithelial Tumors

Cancers ◽

10.3390/cancers13040712 ◽

2021 ◽

Vol 13 (4) ◽

pp. 712

Author(s):

Joohee Lee ◽

Young Seok Cho ◽

Jhingook Kim ◽

Young Mog Shim ◽

Kyung-Han Lee ◽

...

Keyword(s):

Multivariate Analysis ◽

Prognostic Factors ◽

Fdg Pet ◽

Univariate Analysis ◽

Thymic Epithelial Tumors ◽

Epithelial Tumors ◽

Masaoka Stage ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

Background: Imaging tumor FDG avidity could complement prognostic implication in thymic epithelial tumors. We thus investigated the prognostic value of volume-based 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT parameters in thymic epithelial tumors with other clinical prognostic factors. Methods: This is a retrospective study that included 83 patients who were diagnosed with thymic epithelial tumors and underwent pretreatment 18F-FDG PET/CT. PET parameters, including maximum and average standardized uptake values (SUVmax, SUVavg), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), were measured with a threshold of SUV 2.5. Univariate and multivariate analysis of PET parameters and clinicopathologic variables for time-to-progression was performed by using a Cox proportional hazard regression model. Results: There were 21 low-risk thymomas (25.3%), 27 high-risk thymomas (32.5%), and 35 thymic carcinomas (42.2%). Recurrence or disease progression occurred in 24 patients (28.9%). On univariate analysis, Masaoka stage (p < 0.001); histologic types (p = 0.009); treatment modality (p = 0.001); and SUVmax, SUVavg, MTV, and TLG (all p < 0.001) were significant prognostic factors. SUVavg (p < 0.001) and Masaoka stage (p = 0.001) were independent prognostic factors on multivariate analysis. Conclusion: SUVavg and Masaoka stage are independent prognostic factors in thymic epithelial tumors.

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Advancement in Diagnostic Imaging of Thymic Tumors

Cancers ◽

10.3390/cancers13143599 ◽

2021 ◽

Vol 13 (14) ◽

pp. 3599

Author(s):

Francesco Gentili ◽

Ilaria Monteleone ◽

Francesco Giuseppe Mazzei ◽

Luca Luzzi ◽

Davide Del Roscio ◽

...

Keyword(s):

Diagnostic Imaging ◽

Ct Perfusion ◽

Anterior Mediastinum ◽

Actual State ◽

Dual Energy Ct ◽

Mediastinal Tumors ◽

Thymic Epithelial Tumors ◽

Adjacent Structures ◽

Primary Neoplasm ◽

Thymic Tumors

Thymic tumors are rare neoplasms even if they are the most common primary neoplasm of the anterior mediastinum. In the era of advanced imaging modalities, such as functional MRI, dual-energy CT, perfusion CT and radiomics, it is possible to improve characterization of thymic epithelial tumors and other mediastinal tumors, assessment of tumor invasion into adjacent structures and detection of secondary lymph nodes and metastases. This review aims to illustrate the actual state of the art in diagnostic imaging of thymic lesions, describing imaging findings of thymoma and differential diagnosis.

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296 Immune correlates of clinical response to Avelumab in patients with advanced thymic epithelial tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0296 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A323-A323

Author(s):

Yo-Ting Tsai ◽

Arun Rajan ◽

James Gulley ◽

Jeffrey Schlom ◽

Renee Donahue

Keyword(s):

Clinical Response ◽

Mononuclear Cells ◽

Predictive Biomarkers ◽

Lymphocytic Infiltration ◽

Peripheral Blood Mononuclear ◽

Thymic Epithelial Tumors ◽

Link Type ◽

Epithelial Tumors ◽

Immune Correlates ◽

Tcr Diversity

BackgroundThymic epithelial tumors (TET), consisting of thymomas and thymic carcinomas, are PD-L1-expressing tumors characterized by varying degrees of lymphocytic infiltration and a predisposition towards the development of paraneoplastic autoimmunity. As part of a phase I study (NCT01772004), the anti-tumor activity of patients with relapsed, advanced TET to avelumab (anti-PD-L1), was demonstrated and was accompanied by a high frequency of immune related adverse events (irAE). The current study aimed to identify immune related signatures that associate with clinical response and/or the development of irAE.MethodsEight patients with recurrent TET were treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Peripheral blood mononuclear cells (PBMC) were obtained before and during therapy, and interrogated by multicolor flow cytometry to evaluate 123 immune subsets, as well as by T-cell receptor (TCR) sequencing to evaluate TCR diversity.ResultsFour of 8 TET patients had partial responses and 3 had stable disease. All responders developed irAEs that resolved with immunosuppressive therapy, compared to only 1 of 4 non responders. Analyses of PBMC subsets prior to therapy showed that responders had higher absolute lymphocyte counts, and lower frequencies of B cells, Tregs, conventional dendritic cells (cDCs), and NK cells, compared to non-responders. There was also a trend towards a higher level of TCR diversity in those patients who subsequently had a radiological response and developed irAE.ConclusionsImmune profiling identified specific immune measures prior to therapy that differed between responders and non-responders, that may serve as predictive biomarkers to identify patients with relapsed TET most likely to benefit from avelumab and/or to develop irAE.Trial RegistrationNCT01772004Ethics ApprovalAll patients provided written informed consent for participation in a clinical trial that was approved by the Institutional Review Board at the National Cancer Institute (NCT01772004).

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