Mutant GTF2I induces cell transformation and metabolic alterations in thymic epithelial cells
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ABSTRACT:
PROVIDER: PRJNA525777 | ENA |
REPOSITORIES: ENA
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Project description:The pathogenesis of thymic epithelial tumors (TETs) is poorly understood. Recently we reported the frequent occurrence of a missense mutation in the GTF2I gene in TETs and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of normal thymic epithelial cells and upregulated several oncogenic genes. Gtf2i L424H knockin cells exhibited cell transformation, aneuploidy, and increase tumor growth and survival under glucose deprivation or DNA damage. Gtf2i mutation also increased the expression of several glycolytic enzymes, cyclooxygenase-2, and caused modifications of lipid metabolism. Elevated cyclooxygenase-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver that is responsible for transformation of thymic epithelial cells.
2022-03-02 | GSE127909 | GEO
Project description:The molecular mechanisms underlying the pathogenesis of TETs are poorly understood. Recently we reported a common missense mutation on GTF2I gene in thymic tumors and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of thymic epithelial cells and up-regulated several oncogenic genes. Using CRISPR/Cas9n, Gtf2i T1211A knock-in cells exhibited distinct features of cancerous cells including cell transformation, aneuploidy, tumor growth in xenograft, and survival after DNA damage or glucose deprivation. We also observed that Gtf2i mutation increased the expression of several glycolytic enzymes, cyclooxygenase-2, and altered lipid metabolism. Elevated COX-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver mutation that is responsible for transformation of thymic epithelial cells.
2022-03-02 | GSE127907 | GEO
Project description:The molecular mechanisms underlying the pathogenesis of TETs are poorly understood. Recently we reported a common missense mutation on GTF2I gene in thymic tumors and hypothesized that GTF2I mutation might contribute to thymic tumorigenesis. Expression of mutant TFII-I altered the transcriptome of thymic epithelial cells and up-regulated several oncogenic genes. Using CRISPR/Cas9n, Gtf2i T1211A knock-in cells exhibited distinct features of cancerous cells including cell transformation, aneuploidy, tumor growth in xenograft, and survival after DNA damage or glucose deprivation. We also observed that Gtf2i mutation increased the expression of several glycolytic enzymes, cyclooxygenase-2, and altered lipid metabolism. Elevated COX-2 expression by Gtf2i mutation was required for survival under metabolic stress and cellular transformation of thymic epithelial cells. Our findings identify GTF2I mutation as a new oncogenic driver mutation that is responsible for transformation of thymic epithelial cells.
2022-03-02 | GSE127908 | GEO
Project description:GTF2I mutation induces metabolic alterations and cell transformation in thymic epithelial cells [II]
| PRJNA525778 | ENA
Project description:GTF2I mutation induces metabolic alterations and cell transformation in thymic epithelial cells [I]
| PRJNA525773 | ENA
Project description: Not available
| S-EPMC7308410 | biostudies-literature
Project description:Next generation sequencing of 28 thymic epithelial tumors (TETs) revealed a high frequency of GTF2I missense mutation (chr7:74146970T/A) in A thymomas, a relatively indolent subtype. The GTF2I mutation was confirmed in 82% of A and 74% of AB thymomas in a series of 274 TETs but was rare in aggressive subtypes, where recurrent mutations of known cancer genes were identified. Therefore, GTF2I mutation correlated with a better survival. GTF2I Beta and Delta isoforms were expressed in TETs and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas presented a higher number of mutations than thymomas (average 43.5 and 18.4, respectively). Recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1 were identified in thymic carcinomas. These findings will complement the diagnostic work up of these rare tumors, and also help the development of a molecular classification, and assessment of prognosis and treatment strategies. Tumor samples of 286 patients were collected from 4 different institutions: National Cancer Institute (Bethesda MD), Pisa University Hospital (Pisa, Italy), Padua University Hospital (Padua, Italy) and IRCCS Istituto Clinico Humanitas (Rozzano, Italy).
2014-06-24 | E-GEOD-57892 | biostudies-arrayexpress
Project description:Next generation sequencing of 28 thymic epithelial tumors (TETs) revealed a high frequency of GTF2I missense mutation (chr7:74146970T/A) in A thymomas, a relatively indolent subtype. The GTF2I mutation was confirmed in 82% of A and 74% of AB thymomas in a series of 274 TETs but was rare in aggressive subtypes, where recurrent mutations of known cancer genes were identified. Therefore, GTF2I mutation correlated with a better survival. GTF2I Beta and Delta isoforms were expressed in TETs and both mutant isoforms were able to stimulate cell proliferation in vitro. Thymic carcinomas presented a higher number of mutations than thymomas (average 43.5 and 18.4, respectively). Recurrent mutations of known cancer genes, including TP53, CYLD, CDKN2A, BAP1 and PBRM1 were identified in thymic carcinomas. These findings will complement the diagnostic work up of these rare tumors, and also help the development of a molecular classification, and assessment of prognosis and treatment strategies.
2014-06-24 | GSE57892 | GEO
Project description:We previously identified a recurrent mutation L424H in the transcription factor GTF2I in thymic epithelial tumors. The precise role of the GTF2I mutation in these tumors is unclear. Here we describe the generation and characterization of a mouse model in which the Gtf2i L424H mutation was conditionally knocked-in in the Foxn1+ thymic epithelial cells. The Gtf2i mutation impairs development of thymic medulla and maturation of medullary thymic epithelial cells in the young mice and causes tumor formation in the thymus of the aged KI mice. To characterize the molecular features of murine thymomas, we performed digital spatial profiling with GeoMx moue whole transcriptome atlas assay with FFPE thymic tissues of 4 KI and 4 control mice.
2023-01-25 | GSE200784 | GEO
Project description:Within a project aim to define the genomic aberration of thymic epithelial tumors, we performed array CGH in 65 thymic epithelial tumors. Tumor samples were collected during surgery or by image-guided biopsies and immediately frozen. Section from frozen material were cut and stained with Haematoxylin and Eosin. A pathologist reviewed the slides and selected only cases with >80% of cancer cells. Copy number aberrations of a series of 65 thymic epithelial tumors were evaluated using array CGH. Differences in copy number aberrations between different histotypes were evaluated. Significant regions of CN aberrations were defined using GISTIC algorithms.
2014-06-21 | E-GEOD-55852 | biostudies-arrayexpress