Constant GTF2I L424H mutation in micronodular thymoma with lymphoid stroma: genetic evidence supporting its close relationship with type A and AB thymomas

Hsieh, Min‐Shu; Kao, Hua-Lin; Huang, Wen-Chang; Wang, Shuying; Lin, Shin-Ying; Chu, Ping-Yuan; Pan, Chin-Chen; Chou, Teh-Ying; Ho, Hsiang‐Ling; Yeh, Yi‐Chen

doi:10.21203/rs.3.rs-1747099/v1

Cited by 3 publications

(1 citation statement)

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“…Moreover, all RAS mutations were found in GTF2I -mutated cases in the present study, whereas RAS mutations did not always correlate with GTF2I mutations in previous studies ( 12 , 17 ). Recently, Hsieh et al reported that HRAS and KRAS mutations were detected in two of the 12 micronodular thymomas, in addition to the GTF2I mutation ( 35 ). Since micronodular thymoma with lymphoid stroma is genetically close to type A and AB thymomas, their results supported our results that GTF2I mutations were observed in indolent types of thymoma.…”

Section: Discussionmentioning

confidence: 99%

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Shimada¹,

Taniguchi²,

Yamaguchi³

et al. 2023

Transl Lung Cancer Res

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Background: Thymic epithelial tumors (TETs) are prone to developing in East Asian populations.However, little is known about the genomic profile of TETs in East Asian populations, and the genomic aberrations in TETs have not yet been fully clarified. Thus, molecular targeted therapies for patients with TETs have not been established. This prospective study was conducted to explore the genetic abnormalities of surgically resected TETs in a Japanese cohort and to identify clues for carcinogenesis and potential therapeutic targets in TETs.Methods: Genetic profiles of TETs were investigated using fresh-frozen specimens resected from operable cases with TETs. DNA sequencing was performed using a next-generation sequencing (NGS) gene panel test with Ion Reporter™ and CLC Genomics Workbench 11.0. The mutation sites were further confirmed by Sanger sequencing, digital droplet polymerase chain reaction (ddPCR), and TA cloning for validation.Results: Among 43 patients diagnosed with anterior mediastinal tumors between January 2013 and March 2019, NGS and validation analyses were performed in 31 patients [29 thymomas and two thymic cancers (TCs)] who met the study criteria. Of these, 12 cases of thymoma types A, AB, B1, and B2 harbored the general transcription factor 2-I (GTF2I) mutation (L424H). Conversely, the mutation was not detected in type B3 thymoma or TC, suggesting that the GTF2I mutation existed in indolent types of TETs. Rat sarcoma viral oncogene (RAS) mutations were detected in three cases [Harvey RAS (HRAS) in two cases of type AB thymoma

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Section: Discussionmentioning

confidence: 99%

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Shimada¹,

Taniguchi²,

Yamaguchi³

et al. 2023

Transl Lung Cancer Res

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Genome-wide analysis of somatic non-coding mutation patterns and mitochondrial heteroplasmy in type B1 and B2 thymomas

Fujikura,

Correa,

Heck

et al. 2024

Preprint

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IntroductionType B1 and B2 thymomas are lymphocyte-rich malignant tumors with few somatic mutations in protein-coding regions of the nuclear genome; nonetheless, non-coding regions remain uncharacterized. Here, we developed a rigorous tumor isolation method from lymphocyte-rich thymoma tissues and identified somatic mutations in non-coding and mitochondrial DNA.MethodsCD205+CD45-pure tumor cells were isolated from fresh-frozen tissues using DEPArray system. Deep whole-genome sequencing was performed, and recurrent somatic alterations in coding, non-coding, and mitochondria regions were systemically identified by computational framework. The mutations were classified according to gene function, cis-regulatory element, and mutational signature.ResultsThe total number of somatic mutations was approximately 80 times higher in non-coding regions than in coding regions in type B1-2 thymomas (1,671.3 vs. 21.1 per case). Coding mutations were identified in epigenetic regulators, DNA repair genes, and some other genes. Nevertheless, 40% of cases exhibited fewer than four mutations in coding regions. A systematic non-coding analysis identified a total of 405.0 mutations per case on cis-regulatory elements, and detected six recurrent mutations: one interferon regulatory factor (IRF8), two E3 ubiquitin ligases (UBR2andRNF213), and three intergenic regions. Mitochondrial heteroplasmy was observed in 90% of cases, with a significant proportion of mutations located in D-loop region. The single-base substitution pattern was signature 12.ConclusionsNumerous non-coding mutations and mitochondrial heteroplasmy were detected in type B1 and B2 thymomas. Given the paucity of coding mutations observed in this disease entity, disruption of the non-coding landscape and mitochondrial heteroplasmic shift may be the primary cause of thymoma.

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The Molecular Landscape of Thymic Epithelial Tumors: A Comprehensive Review

Elm,

Levidou

2024

IJMS

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Thymic epithelial tumors (TETs) are characterized by their extreme rarity and variable clinical presentation, with the inadequacy of the use of histological classification alone to distinguish biologically indolent from aggressive cases. The utilization of Next Generation Sequencing (NGS) to unravel the intricate genetic landscape of TETs could offer us a comprehensive understanding that is crucial for precise diagnoses, prognoses, and potential therapeutic strategies. Despite the low tumor mutational burden of TETS, NGS allows for exploration of specific genetic signatures contributing to TET onset and progression. Thymomas exhibit a limited mutational load, with prevalent GTF2I and HRAS mutations. On the other hand, thymic carcinomas (TCs) exhibit an elevated mutational burden, marked by frequent mutations in TP53 and genes associated with epigenetic regulation. Moreover, signaling pathway analyses highlight dysregulation in crucial cellular functions and pathways. Targeted therapies, and ongoing clinical trials show promising results, addressing challenges rooted in the scarcity of actionable mutations and limited genomic understanding. International collaborations and data-sharing initiatives are crucial for breakthroughs in TETs research.

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Constant GTF2I L424H mutation in micronodular thymoma with lymphoid stroma: genetic evidence supporting its close relationship with type A and AB thymomas

Cited by 3 publications

References 8 publications

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets

Genome-wide analysis of somatic non-coding mutation patterns and mitochondrial heteroplasmy in type B1 and B2 thymomas

The Molecular Landscape of Thymic Epithelial Tumors: A Comprehensive Review

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