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A mechanistic classification of clinical phenotypes in neuroblastoma (TERT expression threshold cohort)

ABSTRACT: Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCNWT TERTWT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120568 | GEO | 2018/10/25

REPOSITORIES: GEO

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A mechanistic classification of clinical phenotypes in neuroblastoma (telomere maintenance cohort)

Project description:Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCN-WT TERT-WT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.

2018-10-25 | GSE120559 | GEO

A mechanistic classification of clinical phenotypes in neuroblastoma (TERT expression threshold cohort)

Project description:A mechanistic classification of clinical phenotypes in neuroblastoma (TERT expression threshold cohort)

| PRJNA493609 | ENA

A mechanistic classification of clinical phenotypes in neuroblastoma

Project description:Clinical courses of the pediatric tumor neuroblastoma range from fatal progression to spontaneous regression. To gain insights into the pathogenesis of these divergent subtypes, we performed massively parallel sequencing of 416 pretreatment neuroblastomas and assessed telomere maintenance mechanisms in 208/416 cases. We observed that telomere maintenance and mutations in RAS or p53 pathway genes strongly affected disease courses. Fatal outcome occurred only in the presence of telomere maintenance, whereas patients whose tumors lacked such mechanisms had excellent outcome. In patients with telomere maintenance-positive tumors, survival was dramatically inferior when additional RAS/p53 pathway mutations were present. By contrast, spontaneous regression occurred both in the presence and absence of RAS/p53 pathway mutations in patients with telomere maintenance-negative tumors. Together, our data provide a precise mechanistic classification of clinical neuroblastoma phenotypes based on telomere maintenance mechanisms and genetic alterations of the tumor.

| EGAS00001003244 | EGA

A mechanistic classification of clinical phenotypes in neuroblastoma (telomere maintenance cohort)

Project description:A mechanistic classification of clinical phenotypes in neuroblastoma (telomere maintenance cohort)

| PRJNA493570 | ENA

Genomic analysis of mice with endothelium-specific TERT knockout (scRNA-Seq)

Project description:Health of endothelial cells (EC) is fundamental for function of vital organs. However, it has not been established whether EC senescence underlies the pathophysiology of aging. Here, we report a mouse model of EC senescence. Inactivation of telomerase (TERT) expression sets the stage for aging and predisposes cells to replicative senescence. TERT maintains telomere length and has telomere-independent effects on cell transcriptome and physiology. We generated mice with TERT gene knock-out (KO) specifically in EC. We analyzed EC from adipose tissues (AT) and skeletal muscle cells from Tert-EC-KO and control mice raised on either chow or high-calorie diet (HCD) and subjected them to RNA sequencing (RNAseq). Single cell RNAseq data were also obtained for subcutaneous and visceral AT. Preliminary analysis of data deposited online indicates that TERT KO induces premature cell senescence and dysfunction. Moreover, HCD feeding exacerbates the effect of TERT loss. We conclude that the Tert-EC-KO mice are a useful model to study EC senescence and its effects on aging-associated organ dysfunction.

2023-12-05 | GSE239687 | GEO

Genomic analysis of mice with endothelium-specific TERT knockout (RNA-Seq)

Project description:Health of endothelial cells (EC) is fundamental for function of vital organs. There is evidence accumulating that senescence of EC is associated with aging-related diseases. However, it has not been established whether EC senescence underlies the pathophysiology of aging. Here, we report a mouse model of EC senescence. Inactivation of telomerase (TERT) expression sets the stage for aging and predisposes cells to replicative senescence. TERT maintains telomere length and has telomere-independent effects on cell transcriptome and physiology. We generated mice with TERT gene knock-out (KO) specifically in EC. We analyzed EC from adipose tissues (AT) and skeletal muscle cells from Tert-EC-KO and control mice raised on either chow or high-calorie diet (HCD) and subjected them to RNA sequencing (RNAseq). Single cell RNAseq data were also obtained for subcutaneous and visceral AT. Preliminary analysis of data deposited online indicates that TERT KO induces premature cell senescence and dysfunction. Moreover, HCD feeding exacerbates the effect of TERT loss. We conclude that the Tert-EC-KO mice are a useful model to study EC senescence and its effects on aging-associated organ dysfunction.

2023-12-05 | GSE239686 | GEO

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment II

Project description:Telomerase plays a pivotal role in tumorigenesis by both telomere-dependent and telomere-independent activities, although the underlying mechanisms are not completely understood. Using single-sample gene set enrichment analysis (ssGSEA) across 9,264 tumour samples, we observed that expression of telomerase reverse transcriptase (TERT) is closely associated with immune-suppressive signatures. We demonstrated that TERT can activate a subclass of endogenous retroviruses (ERVs) to form double-stranded RNAs (dsRNAs), which were sensed by the RIG-1/MDA5-MAVS signalling pathway and triggered interferon signalling in cancer cells. Furthermore, we showed that TERT-induced ERVs/interferon signalling stimulated the expression of chemokines, including CXCL10, which induced suppressed T cell infiltration with increased percentage of CD4+ and FOXP3+ cells. These data reveal an unanticipated role for telomerase as a transcriptional activator of ERVs and provide strong evidence that TERT-mediated ERVs/interferon signalling contributes to immune suppression in tumours.

2022-02-22 | GSE169713 | GEO

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment I

2022-02-22 | GSE169711 | GEO

TERT activates endogenous retroviruses contributing to immunosuppressive tumour microenvironment III

2022-02-22 | GSE169714 | GEO

Expression of telomerase prevents ALT and maintains telomeric heterochromatin in juvenile brain tumors.

Project description:The up-regulation of a telomere maintenance mechanism (TMM) is an essential step in cancer progression to escape dysfunctional telomeres, senescence and apoptosis. Paediatric brain tumors frequently exhibit Alternative Lengthening of Telomere (ALT) as active TMM, but the mechanisms involved in the induction of ALT in brain tumor cells are not clear. Here, we report a model of juvenile zebrafish brain tumor that progressively develops ALT. We discovered that reduced expression of tert and increase in Terra expression precedes ALT development. Additionally, tumors show persistent telomeric DNA damage and loss of heterochromatin marks. Comparative analysis of gene expression after the rescue of ALT with telomerase and analysis of telomerase positive paediatric brain cancers showed normalization of telomeric heterochromatin and maintenance of telomere length, with reduced expression of genes of the pre-replicative complex as hallmark. Thus our study identifies telomere maintenance mechanisms as major drivers of DNA replication and chromatin status at telomeres in brain cancers.

2022-07-01 | GSE134135 | GEO

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