Mutations of epigenetic regulatory genes are common in thymic carcinomas

Wang, Yisong; Thomas, Anish; Lau, Christopher; Rajan, Arun; Zhu, Yuelin J.; Killian, J. Keith; Petrini, Iacopo; Pham, Trung C.; Morrow, Betsy; Zhong, Xiaogang; Meltzer, Paul S.; Giaccone, Giuseppe

doi:10.1038/srep07336

Cited by 115 publications

(133 citation statements)

References 56 publications

(95 reference statements)

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“…Studies performed in mice with conditional knockout of Dnmt3a revealed a role for DNA methylation in mediating the self-renewal and differentiation of normal hematopoietic stem cells and leukemia stem cells [33]. A functional role of this gene in thymic epithelial tumors emerged from studies that focused on mutation analysis, revealing that DNMT3A is one the most frequently mutated genes in thymic carcinoma [34], and that the mutation p.G728D is associated with B3 thymomas [35]. Similarly, a SNP in the promoter of DNMT3B , namely −579G>T, was associated with TAMG [36], overall suggesting a contribution of de novo DNMTs in thymomas.…”

Section: Discussionmentioning

confidence: 99%

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

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Thymomas are uncommon neoplasms that arise from epithelial cells of the thymus and are often associated with myasthenia gravis (MG), an autoimmune disease characterized by autoantibodies directed to different targets at the neuromuscular junction. Little is known, however, concerning epigenetic changes occurring in thymomas from MG individuals. To further address this issue, we analyzed DNA methylation levels of genes involved in one-carbon metabolism (MTHFR) and DNA methylation (DNMT1, DNMT3A, and DNMT3B) in blood, tumor tissue, and healthy thymic epithelial cells from MG patients that underwent a surgical resection of a thymic neoplasm. For the analyses we applied the methylation-sensitive high-resolution melting technique. Both MTHFR and DNMT3A promoters showed significantly higher methylation in tumor tissue with respect to blood, and MTHFR also showed significantly higher methylation levels in tumor tissue respect to healthy adjacent thymic epithelial cells. Both DNMT1 and DNMT3B promoter regions were mostly hypomethylated in all the investigated tissues. The present study suggests that MTHFR methylation is increased in thymomas obtained from MG patients; furthermore, some degrees of methylation of the DNMT3A gene were observed in thymic tissue with respect to blood.

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Section: Discussionmentioning

confidence: 99%

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Lopomo

Ricciardi

Maestri

et al. 2016

IJMS

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“…Improved genetic 22–24 , epigenetic 25, 26 and transcriptomic 24, 27 analyses have augmented our knowledge about the distinct molecular basis of thymomas and thymic carcinomas. The latter show mutations of epigenetic regulatory genes, 22 methylation patterns 26 and expression profiles of anti-apoptotic genes 27 that clearly distinguish them from thymomas.…”

Section: Novelties In the New Who Classification Of Mediastinal Tumorsmentioning

confidence: 99%

“…The latter show mutations of epigenetic regulatory genes, 22 methylation patterns 26 and expression profiles of anti-apoptotic genes 27 that clearly distinguish them from thymomas. On the other hand, the identification of a highly recurrent point mutation in the GTF2I oncogene in all major thymoma subtypes and thymic carcinomas 23 is a seminal finding that underlines the unique tumor biology of thymic epithelial tumors and lends strong support to the WHO-based subtyping of thymic tumors.…”

Section: Novelties In the New Who Classification Of Mediastinal Tumorsmentioning

confidence: 99%

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

Marx

Chan

Coindre

et al. 2015

Journal of Thoracic Oncology

504

420

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This overview of the 4th edition of the WHO Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumour entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1–B3 thymomas and thymic squamous cell carcinoma are given and will hopefully improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery and oncology; by incorporating state-of-the-art PET/CT images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

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“…Thymic carcinomas have a distinct molecular signature that segregates them from the thymoma subtypes. 6,16–23 Such genetic differences, combined with the histology-based classification system, are clinically relevant for both prognosis and treatment of TETs and may contribute to identification of new molecular targets for therapeutic intervention. 3,7,19,20 …”

Section: Introductionmentioning

confidence: 99%

PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors

Alberobello

Wang

Beerkens

et al. 2016

Journal of Thoracic Oncology

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Introduction Thymic epithelial tumors (TETs) are rare tumors originating from the epithelia of the thymus, and therapeutic options beyond surgery are limited. Pathogenesis of TETs is poorly understood, and the scarcity of model systems for these rare tumors makes the study of their biology very challenging. Methods A new cell line (MP57) was established from a thymic carcinoma specimen and characterized using standard biomarker analysis, as well as next generation sequencing (NGS), and functional assays. Sanger sequencing was used to confirm the mutations identified by NGS. Results MP57 possesses all the tested thymic epithelial markers and is deemed to be a bona fide thymic carcinoma cell line. NGS analysis of MP57 identified a mutation in PIK3R2, a regulatory subunit of PI3K. Further analysis identified different mutations in multiple PI3K subunits in another cell line and several primary thymic carcinoma samples, including two catalytic subunits (PIK3CA and PIK3CG) and another regulatory subunit (PIK3R4). Inhibiting PI3K with GDC0941 resulted in in vitro antitumor activities in TET cells carrying mutant PI3K subunits. Conclusions Alterations of PI3K, due to mutations in its catalytic or regulatory subunits, is observed in a subgroup of TETs, in particular thymic carcinomas. Targeting PI3K may be an effective strategy to treat these tumors.

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Mutations of epigenetic regulatory genes are common in thymic carcinomas

Cited by 115 publications

References 56 publications

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

Gene-Specific Methylation Analysis in Thymomas of Patients with Myasthenia Gravis

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes

PI3K as a Potential Therapeutic Target in Thymic Epithelial Tumors

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