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Open AccessEditorial

The Way Ahead: Lessons Learned from Decades of Cancer Research on Thymomas and Thymic Carcinomas

by Philipp Ströbel and Alexander Marx

Cancers 2024, 16(5), 1040; https://doi.org/10.3390/cancers16051040 - 4 Mar 2024

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Abstract

The history of thymoma (TH) research begins in the early 20th century, when Bell first recognized the epithelial nature of these tumors and their association with myasthenia gravis (MG) [...] Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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Research

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18 pages, 2673 KiB

Open AccessArticle

Aberrant DNA Methylation of NPTX2 as an Indicator of Malignant Behavior in Thymic Epithelial Tumors

by Kazuya Kondo, Kyoka Muguruma, Shiho Soejima, Chikako Takai, Koichiro Kenzaki, Naoya Kawakita, Hiroaki Toba and Hiromitsu Takizawa

Cancers 2024, 16(2), 329; https://doi.org/10.3390/cancers16020329 - 11 Jan 2024

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Abstract

Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands [...] Read more.

Thymic epithelial tumors (TET) consist of thymomas, thymic carcinoma (TC), and neuroendocrine tumors of the thymus (NECTT). Genetic and epigenetic alterations in TET have been the focus of recent research. In the present study, genome-wide screening was performed on aberrantly methylated CpG islands in TET, and this identified neuronal pentraxin 2 (NTPX2) as a significantly hypermethylated CpG island in TC relative to thymomas. NPTX2 is released from pre-synaptic cells in response to neuronal activity/seizure, and plays a role in host immunity and acute inflammation. TET samples were obtained from 38 thymomas, 25 TC, and 6 NECTT. The DNA methylation, mRNA, and protein expression levels of NPTX2 were examined. The DNA methylation rate of the NPTX2 gene was significantly higher in TC than in the normal thymus and thymomas, except B3. The mRNA expression level of NPTX2 was lower in TC than in the normal thymus. An inverse relationship was observed between mRNA expression levels and methylation levels. Relapse-free survival was shorter in patients with high NPTX2 DNA methylation levels than in those with low DNA methylation levels. NECTT showed very high mRNA and protein expression levels and low DNA methylation levels of NPTX2. NPTX2 may function as a tumor suppressor in TC, and have an oncogenic function in NECTT. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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16 pages, 10901 KiB

Open AccessArticle

Thymic Carcinoma: Unraveling Neuroendocrine Differentiation and Epithelial Cell Identity Loss

by Yosuke Yamada, Kosuke Iwane, Yuki Nakanishi and Hironori Haga

Cancers 2024, 16(1), 115; https://doi.org/10.3390/cancers16010115 - 25 Dec 2023

Cited by 1 | Viewed by 961

Abstract

Background: The histogenesis of thymic epithelial tumors (TETs) has been a subject of debate. Recent technological advancements have revealed that thymic carcinomas often exhibit a phenotype akin to tuft cells, which is a subset of medullary TECs. Here, we further explored the gene [...] Read more.

Background: The histogenesis of thymic epithelial tumors (TETs) has been a subject of debate. Recent technological advancements have revealed that thymic carcinomas often exhibit a phenotype akin to tuft cells, which is a subset of medullary TECs. Here, we further explored the gene expression signatures of thymic carcinomas in relation to tuft cells and their kinships—ionocytes and neuroendocrine cells (neuroendocrine group). Methods: We analyzed a single-cell RNA sequencing dataset from the normal human thymus. Concurrently, we examined publicly available datasets on the mRNA expression and methylation status of TECs and lung cancers. Real-time quantitative PCR was also conducted with our tissue samples. Results: Thymic carcinomas displayed a neuroendocrine phenotype biased toward tuft cells and ionocytes. When exploring the possible regulators of this phenotype, we discovered that HDAC9 and NFATC1 were characteristically expressed in the neuroendocrine group in adult TECs and thymic carcinomas. Additionally, the pan-thymic epithelium markers, exemplified by PAX9 and SIX1, were significantly suppressed in thymic carcinomas. Conclusions: Thymic carcinomas might be characterized by unique neuroendocrine differentiation and loss of identity as thymic epithelial cells. Future studies investigating the role of HDAC9 and NFATC1 in thymic epithelium are warranted to explore their potential as therapeutic targets in TETs. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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Review

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11 pages, 246 KiB

Open AccessReview

A Re-Examination of Neoadjuvant Therapy for Thymic Tumors: A Long and Winding Road

by Fenghao Yu, Zhitao Gu, Xuefei Zhang, Ning Xu, Xiuxiu Hao, Changlu Wang, Yizhuo Zhao, Teng Mao and Wentao Fang

Cancers 2024, 16(9), 1680; https://doi.org/10.3390/cancers16091680 - 26 Apr 2024

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Abstract

For most patients with advanced thymic epithelial tumors (TETs), a complete resection is a strong indicator of a better prognosis. But sometimes, primary surgery is unsatisfactory, and preoperative therapy is needed to facilitate complete resection. Neoadjuvant chemotherapy is the most used form of [...] Read more.

For most patients with advanced thymic epithelial tumors (TETs), a complete resection is a strong indicator of a better prognosis. But sometimes, primary surgery is unsatisfactory, and preoperative therapy is needed to facilitate complete resection. Neoadjuvant chemotherapy is the most used form of preoperative therapy. But studies on neoadjuvant chemotherapy have included mainly patients with thymoma; its efficacy in patients with thymic carcinoma is less known. Neoadjuvant chemoradiation has also been explored in a few studies. Novel therapies such as immunotherapy and targeted therapy have shown efficacy in patients with recurrent/metastatic TETs as a second-line option; their role as preoperative therapy is still under investigation. In this review, we discuss the existing evidence on preoperative therapy and the insight it provides for current clinical practice and future studies. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

18 pages, 297 KiB

Open AccessReview

Immunotherapy for Thymomas and Thymic Carcinomas: Current Status and Future Directions

by Arun Rajan, Alisa K. Sivapiromrat and Meredith J. McAdams

Cancers 2024, 16(7), 1369; https://doi.org/10.3390/cancers16071369 - 30 Mar 2024

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Abstract

Thymic epithelial tumors are a histologically diverse group of cancers arising from the epithelial compartment of the thymus. These tumors are characterized by a low tumor mutation burden, a lack of actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery [...] Read more.

Thymic epithelial tumors are a histologically diverse group of cancers arising from the epithelial compartment of the thymus. These tumors are characterized by a low tumor mutation burden, a lack of actionable genomic changes, and, especially with thymomas, defects in immune tolerance. Surgery is the mainstay of the management of resectable disease, whereas advanced, unresectable tumors are treated with platinum-based chemotherapy. Disease recurrence can occur months to years after frontline treatment. Although several options are available for conventional treatment of recurrent thymic tumors, response rates are generally low, and treatment-related toxicity can affect quality of life. A subset of patients benefit from biologic therapies, but there remains an unmet need for the development of new treatments. Immune checkpoint inhibitors are safe, clinically active, and have contributed to an improvement in survival for patients with a wide variety of cancers. However, the application of these revolutionary treatments for thymic cancers is limited to their use for the management of recurrent thymic carcinoma because of the risk of immune toxicity. In this paper, we review the current uses of immunotherapy for the management of thymic epithelial tumors and highlight potential strategies to improve safety and broaden the application of these treatments for patients with thymic cancers. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

16 pages, 3652 KiB

Open AccessReview

Non-Mutational Key Features in the Biology of Thymomas

by Stefan Küffer, Denise Müller, Alexander Marx and Philipp Ströbel

Cancers 2024, 16(5), 942; https://doi.org/10.3390/cancers16050942 - 26 Feb 2024

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Abstract

Thymomas (THs) are a unique group of heterogeneous tumors of the thymic epithelium. In particular, the subtypes B2 and B3 tend to be aggressive and metastatic. Radical tumor resection remains the only curative option for localized tumors, while more advanced THs require multimodal [...] Read more.

Thymomas (THs) are a unique group of heterogeneous tumors of the thymic epithelium. In particular, the subtypes B2 and B3 tend to be aggressive and metastatic. Radical tumor resection remains the only curative option for localized tumors, while more advanced THs require multimodal treatment. Deep sequencing analyses have failed to identify known oncogenic driver mutations in TH, with the notable exception of the GTF2I mutation, which occurs predominantly in type A and AB THs. However, there are multiple alternative non-mutational mechanisms (e.g., perturbed thymic developmental programs, metabolism, non-coding RNA networks) that control cellular behavior and tumorigenesis through the deregulation of critical molecular pathways. Here, we attempted to show how the results of studies investigating such alternative mechanisms could be integrated into a current model of TH biology. This model could be used to focus ongoing research and therapeutic strategies. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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19 pages, 748 KiB

Open AccessReview

What Have We Learned from Molecularly Informed Clinical Trials on Thymomas and Thymic Carcinomas—Current Status and Future Directions?

by Rohan Maniar and Patrick J. Loehrer, Sr.

Cancers 2024, 16(2), 416; https://doi.org/10.3390/cancers16020416 - 18 Jan 2024

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Abstract

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The [...] Read more.

Thymic epithelial tumors (TETs), which include thymomas and thymic carcinomas, are a rare, heterogeneous group of malignancies that originate from the thymus gland. As an important organ of immune cell development, thymic tumors, particularly thymomas, are often associated with paraneoplastic autoimmune disorders. The advances in targeted therapies for both solid and hematologic malignancies have resulted in improved patient outcomes, including better and more durable efficacy and improved toxicity. Targeted therapies have also been investigated in the treatment of TETs, though the results have largely been modest. These have included somatostatin-receptor-targeting therapies, KIT- and EGFR-directed tyrosine kinase inhibitors, epigenetic modulators, anti-angiogenesis agents, and agents targeting the cell proliferation and survival pathways and cell cycle regulators. Numerous investigated treatments have failed or underperformed due to a lack of a strong biomarker of efficacy. Ongoing trials are attempting to expand on previous experiences, including the exploration of effective drugs in early-stage disease. Novel combination therapy strategies are also undergoing evaluation, with the goal of augmenting efficacy and understanding the toxicity while expanding the biomarkers of efficacy and safety. With advances in technology to improve target identification and drug delivery, old targets may become new opportunities, and the subsequently developed drugs may find their place in the treatment of thymic tumors. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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18 pages, 357 KiB

Open AccessReview

Molecular and Functional Key Features and Oncogenic Drivers in Thymic Carcinomas

by Serena Barachini, Eleonora Pardini, Irene Sofia Burzi, Gisella Sardo Infirri, Marina Montali and Iacopo Petrini

Cancers 2024, 16(1), 166; https://doi.org/10.3390/cancers16010166 - 29 Dec 2023

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Abstract

Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most [...] Read more.

Thymic epithelial tumors, comprising thymic carcinomas and thymomas, are rare neoplasms. They differ in histology, prognosis, and association with autoimmune diseases such as myasthenia gravis. Thymomas, but not thymic carcinomas, often harbor GTF2I mutations. Mutations of CDKN2A, TP53, and CDKN2B are the most common thymic carcinomas. The acquisition of mutations in genes that control chromatin modifications and epigenetic regulation occurs in the advanced stages of thymic carcinomas. Anti-angiogenic drugs and immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have shown promising results for the treatment of unresectable tumors. Since thymic carcinomas are frankly aggressive tumors, this report presents insights into their oncogenic drivers, categorized under the established hallmarks of cancer. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

14 pages, 1930 KiB

Open AccessReview

The Role of Gene Fusions in Thymic Epithelial Tumors

by Anja C. Roden

Cancers 2023, 15(23), 5596; https://doi.org/10.3390/cancers15235596 - 27 Nov 2023

Cited by 1 | Viewed by 1049

Abstract

Thymic epithelial tumors (TET) are rare and large molecular studies are therefore difficult to perform. However, institutional case series and rare multi-institutional studies have identified a number of interesting molecular aberrations in TET, including gene fusions in a subset of these tumors. These [...] Read more.

Thymic epithelial tumors (TET) are rare and large molecular studies are therefore difficult to perform. However, institutional case series and rare multi-institutional studies have identified a number of interesting molecular aberrations in TET, including gene fusions in a subset of these tumors. These gene fusions can aid in the diagnosis, shed light on the pathogenesis of a subset of tumors, and potentially may provide patients with the opportunity to undergo targeted therapy or participation in clinical trials. Gene fusions that have been identified in TET include MAML2 rearrangements in 50% to 56% of mucoepidermoid carcinomas (MAML2::CRTC1), 77% to 100% of metaplastic thymomas (YAP1::MAML2), and 6% of B2 and B3 thymomas (MAML2::KMT2A); NUTM1 rearrangements in NUT carcinomas (most commonly BRD4::NUTM1); EWSR1 rearrangement in hyalinizing clear cell carcinoma (EWSR1::ATF1); and NTRK rearrangement in a thymoma (EIF4B::NTRK3). This review focuses on TET in which these fusion genes have been identified, their morphologic, immunophenotypic, and clinical characteristics and potential clinical implications of the fusion genes. Larger, multi-institutional, global studies are needed to further elucidate the molecular characteristics of these rare but sometimes very aggressive tumors in order to optimize patient management, provide patients with the opportunity to undergo targeted therapy and participate in clinical trials, and to elucidate the pathogenesis of these tumors. Full article

(This article belongs to the Special Issue Thymic Tumors: New Developments and Future Directions in Molecularly Informed Therapies)

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