Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors

Petrini, Iacopo; Wang, Yisong; Zucali, Paolo Andrea; Lee, Hye Seung; Pham, Trung C.; Voeller, Donna; Meltzer, Paul S.; Giaccone, Giuseppe

doi:10.1158/1078-0432.ccr-12-3260

Cited by 37 publications

(26 citation statements)

References 38 publications

(59 reference statements)

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“…The molecular landscape of TETs is just beginning to be uncovered and only a handful of molecular characterization studies have been conducted in these tumors (12,13,28–30). Petrini and colleagues firstly reported that next-generation sequencing in TETs firstly identified a missense mutation in GTF2I at high frequency in type A thymomas with better survival (12).…”

Section: Discussionmentioning

confidence: 99%

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

Lee

Jang

Shah

et al. 2017

Clinical Cancer Research

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PURPOSE To reconcile the heterogeneity of thymic epithelial tumors (TETs) and gain deeper understanding of the molecular determinants of TETs, we set out to establish a clinically relevant molecular classification system for these tumors. EXPERIMENTAL DESIGN Molecular subgrouping of TETs was performed in 120 patients from The Cancer Genome Atlas using a multidimensional approach incorporating analyses of DNA mutations, mRNA expression, and somatic copy number alterations (SCNA), and validated in two independent cohorts. RESULTS Four distinct molecular subtypes of TETs were identified. The most commonly identified gene mutation was a missense mutation in General Transcription Factor II-I (GTF2I group), which was present in 38% of patients. The next group was identified by unsupervised mRNA clustering of GTF2I wild type tumors and represented TETs enriched in expression of genes associated with T cell signaling (TS group; 33%). The remaining 2 groups were distinguished by their degree of chromosomal stability (CS group; 8%) or instability (CIN group; 21%) based upon SCNA analyses. Disease-free survival and overall survival were favorable in the GTF2I group and unfavorable in the CIN group. These molecular subgroups were associated with TET histology and clinical features including disease-free survival. Finally, we demonstrate high expression of PD1 mRNA and correlation of PD1 and CD8A in the TS subgroup. CONCLUSIONS Molecular subtyping of TETs is associated with disease-free and overall survival. Classification of TETs by a molecular framework could aid in the refinement of staging, and in discovery and development of rational treatment options for patients with TETs.

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Section: Discussionmentioning

confidence: 99%

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

Lee

Jang

Shah

et al. 2017

Clinical Cancer Research

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“…Real-time PCRs were operated on the ABI 7900HT fast real-time PCR system (Applied Biosystems). Fold changes in mRNA expression were calculated by the 2 − ΔCt method 46 .…”

Section: Methodsmentioning

confidence: 99%

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors

et al. 2014

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We analyzed 28 thymic epithelial tumors (TETs) using next-generation sequencing and identified a missense mutation (chromosome 7 c.74146970T>A) in GTF2I at high frequency in type A thymomas, a relatively indolent subtype. In a series of 274 TETs, we detected the GTF2I mutation in 82% of type A and 74% of type AB thymomas but rarely in the aggressive subtypes, where recurrent mutations of known cancer genes have been identified. Therefore, GTF2I mutation correlated with better survival. GTF2I β and δ isoforms were expressed in TETs, and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas carried a higher number of mutations than thymomas (average of 43.5 and 18.4, respectively). Notably, we identified recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1, in thymic carcinomas. These findings will complement the diagnostic assessment of these tumors and also facilitate development of a molecular classification and assessment of prognosis and treatment strategies.

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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 molecular revolution has just begun to approach thymic epithelial tumors (TETs), 23, 25 but the understanding of their biology is far away from the level reached in many hematological and solid tumors. However, The Cancer Genome Atlas (TCGA) has recently included TETs for analysis of genetic, transcriptomic, and epigenetic changes in relation to clinicopathologic and follow-up data.…”

Section: Perspectives and Challengesmentioning

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

509

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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Copy Number Aberrations of Genes Regulating Normal Thymus Development in Thymic Epithelial Tumors

Cited by 37 publications

References 38 publications

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

Genomic Analysis of Thymic Epithelial Tumors Identifies Novel Subtypes Associated with Distinct Clinical Features

A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors

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

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