SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE175893 | GEO | 2021/06/02
REPOSITORIES: GEO
Similar Datasets
Project description:SMARCA4-deficient rhabdoid tumours show intermediate molecular features between SMARCB1-deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type.
| PRJNA734259 | ENA
Project description:Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.
| S-EPMC7847432 | biostudies-literature
Project description:Purpose: Molecular characterization of ECRT-SMARCA4 tumours and their place within the constellation of ECRT-SMARCB1, ATRT and SCCOHT Methods: Total RNA was obtained from 72 fresh-frozen tumour samples using the Qiagen RNAeasy kit (Qiagen, Venlo, Netherlands), according to the manufacturer’s procedure. Barcode Illumina compatible libraries were generated from 750 ng of total RNA for each sample using the TruSeq Stranded mRNA Library Preparation Kit (Illumina). Libraries were sequenced using the Illumina HiSeq 2500 platform. RNA-seq data pre-processing was performed using an in-house pipeline developed at the Curie Institute Bioinformatics Core Facility. Read mapping and counting were performed using STAR, version 2.5.3) and the hg19 version of the human reference genome. Results: Dimensionality reduction and hierarchical clustering algorithms applied to the transcriptomics dataset show that ECRT-SMARCA4 display molecular features intermediate between SCCOHT and ECRTS-MARCB1.
2021-06-02 | GSE175891 | GEO
Project description:Extra-cranial rhabdoid tumors (RT) are highly aggressive malignancies of infancy, characterized by undifferentiated histological features and loss of SMARCB1 expression. The diagnosis is all the more challenging that other poorly differentiated cancers lose SMARCB1 expression, such as epithelioid sarcomas (ES), renal medullary carcinomas (RMC) or undifferentiated chordomas (UC). Moreover, late cases occurring in adults are now increasingly reported, raising the question of differential diagnoses and emphasizing nosological issues. To address this issue, we have analyzed the expression profiles of a training set of 32 SMARCB1-deficient tumors (SDT), with ascertained diagnosis of RT (n = 16, all < 5 years of age), ES (n = 8, all > 10 years of age), UC (n = 3) and RMC (n = 5). As compared with other SDT, RT are characterized by an embryonic signature, and up-regulation of key-actors of de novo DNA methylation processes. Using this signature, we then analysed the expression profiling of 37 SDT to infer the appropriate diagnosis. Thirteen adult onset tumors showed strong similarity with pediatric RT, in spite of older age; by exome sequencing, these tumors also showed genomic features indistinguishable from pediatric RT. In contrary, 8 tumors were reclassified within carcinoma, ES or UC categories, while the remaining could not be related to any of those entities. Our results demonstrate that embryonic signature is shared by all RT, whatever the age at diagnosis; they also illustrate that many adult-onset SDT of ambiguous histological diagnosis are clearly different from RT. Finally, our study paves the way for the routine use of expression-based signatures to give accurate diagnosis of SDT.
| S-EPMC5470964 | biostudies-literature
Project description:Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.
| S-EPMC7876656 | biostudies-literature
Project description:Rhabdoid tumours (RTs) are highly aggressive tumours of infancy, frequently localized in the central nervous system (CNS) where they are termed atypical teratoid/rhabdoid tumours (AT/RTs) and characterized by bi-allelic inactivation of the SMARCB1 tumour suppressor gene. In this study, by temporal control of tamoxifen injection in Smarcb1(flox/flox);Rosa26-Cre(ERT2) mice, we explore the phenotypes associated with Smarcb1 inactivation at different developmental stages. Injection before E6, at birth or at 2 months of age recapitulates previously described phenotypes including embryonic lethality, hepatic toxicity or development of T-cell lymphomas, respectively. Injection between E6 and E10 leads to high penetrance tumours, mainly intra-cranial, with short delays (median: 3 months). These tumours demonstrate anatomical, morphological and gene expression profiles consistent with those of human AT/RTs. Moreover, intra- and inter-species comparisons of tumours reveal that human and mouse RTs can be split into different entities that may underline the variety of RT cells of origin.
| S-EPMC4738337 | biostudies-literature
Project description:In this study, DCAF5, a substrate receptor that has been shown to modulate the levels of SWI/SNF subunits, which are components of a chromatin remodeling complex. Here we preformed ubiquitinome proteomics to discover the underlying response of DCAF5 loss on ubiquitylation of SWI/SNF subunits. Furthermore, we determine what sites on SWI/SNF components decrease in ubiquitylation upon DCAF5 loss.
2024-03-25 | PXD046463 | Pride
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:BackgroundRenal cell carcinoma with rhabdoid features (RCC-RF) is an aggressive histologic variant in the adults and is usually unresponsive to standard chemotherapy.MethodsExpression of SMARCB1/INI1 was examined in primary RCC-RF (n = 5). Stable INI1 with/without prostaglandin E2 receptor 1 (EP1) knockdown cell lines were created in the ACHN and 786-O RCC cell lines and measured for epidermal growth factor receptor (EGFR)-related signaling pathways. Chemosensitivity to targeted drugs in vitro was tested after knocking down of INI1 in both cell lines. The outcome of co-targeting of INI1 and EP1 in RCC was examined using a tumorigenicity assay.ResultsExpression of INI1 was markedly reduced at both transcriptional and translational levels in primary RCC-RF. Immunohistochemical expression of INI1 protein was lost in the nuclei of rhabdoid cells compared with conventional RCC (n = 8). Using two cell lines with different genetic background, we showed that knocking down of INI1 activates the EGFR signaling with up-regulated AKT and ERK pathways and sensitizes cancer cells to Erlotinib treatment in vitro. However, cell-line dependent effects were also demonstrated with reference to impact of INI1 or EP1 on cell growth, migration and response to Gefitinib or Everolimus treatment in vitro.ConclusionInactivation of INI1 may play a role in the pathogenesis of RCC-RF. Erlotinib is recommended in the management of patients with INI1-related RCC.
| S-EPMC8273225 | biostudies-literature
Project description:Despite the genetic inactivation of SMARCA4, a core component of the SWI/SNF-complex commonly found in cancer, there are no therapies that effectively target SMARCA4-deficient tumours. Here, we show that, unlike the cells with activated MYC oncogene, cells with SMARCA4 inactivation are refractory to the histone deacetylase inhibitor, SAHA, leading to the aberrant accumulation of H3K27me3. SMARCA4-mutant cells also show an impaired transactivation and significantly reduced levels of the histone demethylases KDM6A/UTX and KDM6B/JMJD3, and a strong dependency on these histone demethylases, so that its inhibition compromises cell viability. Administering the KDM6 inhibitor GSK-J4 to mice orthotopically implanted with SMARCA4-mutant lung cancer cells or primary small cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), had strong anti-tumour effects. In this work we highlight the vulnerability of KDM6 inhibitors as a characteristic that could be exploited for treating SMARCA4-mutant cancer patients.
| S-EPMC8280185 | biostudies-literature