RNA sequencing data from primary atypical teratoid rhabdoid tumor (ATRT) samples
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE160748 | GEO | 2020/12/18
REPOSITORIES: GEO
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Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
2016-03-02 | GSE70460 | GEO
Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets. 49 ATRT samples were selected for RNA extraction and hybridization on Affymetrix Affymetrix Human Genome U133 Plus 2.0 Arrays. ---------------------------------------- This submission consists of the expression data for 49 of 170 samples only
2016-03-02 | E-GEOD-70678 | biostudies-arrayexpress
Project description:Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1 deficient cases
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Project description:Genome wide DNA methylation profiling of ATRTs and extracranial malignant rhabdoid tumors (eMRTs) samples harboring mutations in SMARCA4 and of small cell carcinoma of the ovary hypercalcemic type (SCCOHT) was performed . The Illumina Infinium HumanMethylation450 BeadChip and the Illumina Infinium MethylationEPIC arrays were used to obtain DNA methylation profiles across approximately 450,000 CpGs and 850,000 CpGs, respectively, in FFPE derived tumor samples. In total n=14 ATRT, n=6 eMRTs and n=28 SCCOHT samples were analyzed.
2020-12-18 | GSE161692 | GEO
Project description:Atypical teratoid/rhabdoid tumors (AT/RT) are highly aggressive CNS-tumors of infancy and early childhood. Hallmark is the surprisingly simple genomics with a truncating mutation in the SMARCB1 gene as the oncogenic driver. Nevertheless, AT/RTs are infiltrated by immune cells and even clonally expanded T-cells. However, it is unclear, what T-cells might recognize on AT/RT cells. Here, we report a comprehensive analysis of naturally presented HLA-class-I and class-II ligands on n=23 AT/RTs. MS-based analysis of the HLA-ligandome revealed 55 class-I and 139 class-II peptides from tumor-associated proteins.
2022-05-31 | PXD033935 | Pride
Project description:Atypical teratoid/rhabdoid tumor (ATRT) is one of the most common brain tumors in infants. Although the prognosis of ATRT patients is poor, some patients respond favorably to current treatments, suggesting molecular inter-tumor heterogeneity. To investigate this further, we genetically and epigenetically analyzed a large series of human ATRTs. Three distinct molecular subgroups of ATRTs, associated with differences in demographics, tumor location, and type of SMARCB1 alterations, were identified. Whole-genome DNA and RNA sequencing found no recurrent mutations in addition to SMARCB1 that would explain the differences between subgroups. Whole-genome bisulfite sequencing and H3K27Ac chromatin-immunoprecipitation sequencing of primary tumors, however, revealed clear differences, leading to the identification of subgroup-specific regulatory networks and potential therapeutic targets.
2016-03-02 | GSE70678 | GEO
Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
2024-09-05 | GSE213249 | GEO
Project description:Loss of function mutations in SMARCB1 are prevalent in pediatric atypical teratoid rhabdoid tumors (ATRTs) and confer an oncogenic dependency on EZH2, providing a compelling rationale for treating these genetically defined cancers via EZH2 inhibition (EZH2i). EZH2i results in tumor regression in SMARCB1-deficient tumors in preclinical studies, but the molecular mechanism has not been fully elucidated. Here we found that the sensitivity of SMARCB1-deficient tumors to EZH2i is associated with the viral mimicry response that depends on both double-stranded RNA (dsRNA) and cytoplasmic DNA sensing pathways. Unlike other epigenetic therapies targeting transcriptional repressors, viral mimicry by EZH2i in SMARCB1-deficient tumors is not triggered by crypt initiation of endogenous retroelements, but rather mediated by increased expression of genes enriched for intronic inverted-repeat Alu (IR-Alu) elements. Interestingly, we found that interferon-stimulated genes (ISGs) are highly enriched for dsRNA-forming intronic IR-Alu elements, suggesting a positive feedback loop whereby interferon response leads to dsRNA formation from intronic ISGs and activation of viral mimicry. Moreover, EZH2i in ATRT cells also enhances the expression of full-length LINE-1 elements, leading to genomic instability and cGAS/STING response in a process dependent on reverse transcriptase activity. Supporting this mechanism, co-depletion of dsRNA sensing and cytoplasmic DNA sensing completely rescues the viral mimicry response to EZH2i in SMARCB1-deficient tumors.
2024-09-05 | GSE213248 | GEO
Project description:Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterised by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.
2024-09-08 | GSE276501 | GEO
Project description:Atypical teratoid/rhabdoid tumor (AT/RT) is the most common malignant brain tumor in infants and is characterized by loss of nuclear SMARCB1 protein expression. Recent studies show that AT/RTs comprise three molecular subgroups with epigenetic differences, including distinct expression patterns of genes involved in ciliogenesis, but little is known on the functional role of primary cilia in the biology of AT/RT. Here, we show that primary cilia are present across all AT/RT subgroups with specific enrichment in AT/RT-TYR patient samples. Furthermore, we demonstrate that primary ciliogenesis contributes to AT/RT biology in vitro and in vivo. Specifically, we observed a significant decrease in proliferation and clonogenicity following disruption of primary ciliogenesis in AT/RT cell line models. Apoptosis was significantly increased via the induction of STAT1 and DR5 signaling, as detected by proteogenomic profiling. In a Drosophila model of SMARCB1 deficiency, concomitant knockdown of several cilia-associated genes resulted in a substantial shift of the lethal phenotype with more than 20% of flies reaching adulthood. Finally, we demonstrated significantly extended survival in an orthotopic xenograft mouse model of AT/RT upon disruption of primary ciliogenesis, confirming a survival benefit across different species with SMARCB1 deficiency. Altogether, our findings indicate that targeting primary ciliogenesis or its downstream signaling may constitute a novel therapeutic approach for AT/RT.
2022-10-14 | PXD027211 | Pride