DNA methylation profiling of CNS tumors of the novel CNS embryonal tumor type ET, PLAGL
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE212621 | GEO | 2022/11/04
REPOSITORIES: GEO
Similar Datasets
Project description:DNA methylation profiling of CNS tumors of the novel CNS embryonal tumor type ET, PLAGL
| PRJNA876274 | ENA
Project description:Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells (NPC) during early development. Here we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal and embryonal CNS tumor cell lines, a selective infection of CNS tumor cells, followed by a massive necrotic tumor cell death, was verified. Notably, ZIKVBR was more efficient in destroying CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, reduced tumor burden, fewer metastasis and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level were more susceptible to ZIKVBR oncolytic effects. Altogether, these preclinical findings indicate that ZIKV could be an efficient oncolytic agent to treat aggressive forms of embryonal CNS tumors. Considering the poor effectiveness and severe side effects of available treatments for these tumors and that most ZIKV infections are asymptomatic, our findings open new avenues for novel therapies.
2017-12-25 | GSE103935 | GEO
Project description:Tremendous progress has recently been made in both molecular subgrouping, and the establishment of prognostic biomarkers for embryonal brain tumors, particularly medulloblastoma. Several prognostic biomarkers that were initially identified in retrospective cohorts of medulloblastoma, including MYC and MYCN amplification, nuclear ?-catenin accumulation, and chromosome 17 aberrations have now been validated in clinical trials. Moreover, molecular subgroups based on distinct transcriptome profiles have been consistently reported from various groups on different platforms demonstrating that the concept of distinct medulloblastoma subgroups is very robust. Well-described subgroups of medulloblastomas include tumors showing wingless signaling pathway (Wnt) activation, and another characterized by sonic hedgehog pathway activity. Two or more additional subgroups were consistently reported to contain the vast majority of high-risk tumors, including most tumors with metastatic disease at diagnosis and/or large cell/anaplastic histology. Several years ago, atypical teratoid rhabdoid tumor (AT/RT) was recognized as a separate entity based on its distinct biology and particularly aggressive clinical behavior. These tumors may occur supra or infratentorially and are usually found to have genetic alterations of SMARCB1 (INI1/hSNF5), a tumor suppressor gene located on chromosome 22q. Subsequent loss of SMARCB1 protein expression comprises a relatively specific and sensitive diagnostic marker for AT/RT. For CNS primitive neuroectodermal tumors (CNS PNETs), a consistent finding has been that they are molecularly distinct from medulloblastoma. Furthermore, a distinct fraction of CNS PNETs with particularly poor prognosis only occurring in young children was delineated, which was previously labeled ependymoblastoma or embryonal tumor with abundant neuropil and true rosettes (ETANTR) and which is morphologically characterized by the presence of multilayered "ependymoblastic" rosettes. This group of tumors shows a unique cytogenetic abnormality not seen in other brain tumors: focal amplification of a micro-RNA cluster at chromosome 19q13.42, which has never been found to be amplified in other CNS PNETs, medulloblastoma or AT/RT. In summary, these consistent findings have significantly contributed to our ability to sub-classify embryonal brain tumors into clinically and biologically meaningful strata and, for some of the subgroups, have led to the identification of specific targets for future development of molecularly targeted therapies.
| S-EPMC4512653 | biostudies-literature
Project description:Ependymal tumors across age groups are currently classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patients' outcome. We aimed at establishing a uniform molecular classification using DNA methylation profiling. Nine molecular subgroups were identified in a large cohort of 500 tumors, 3 in each anatomical compartment of the CNS, spine, posterior fossa, supratentorial. Two supratentorial subgroups are characterized by prototypic fusion genes involving RELA and YAP1, respectively. Regarding clinical associations, the molecular classification proposed herein outperforms the current histopathological classification and thus might serve as a basis for the next World Health Organization classification of CNS tumors.
2015-05-21 | GSE65362 | GEO
Project description:Central nervous system primitive neuroectodermal tumors (CNS PNET) and medulloblastomas are both embryonal tumors that predominantly occur in children. We used microarrays to analyse a cohort of CNS PNETs and medulloblastomas to identify gene expression related to tumor subgroups.
2013-05-01 | GSE19404 | GEO
Project description:BACKGROUND:Embryonal tumors in the central nervous system (CNS) are primary, aggressive, and poorly differentiated pediatric brain tumors. We identified forkhead box R2 (FOXR2) as an oncogene for medulloblastoma through a transposon-based insertional mutagenesis screen. FOXR2 translocation has been identified in a subset of human embryonal tumors of the CNS, designated as CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2); however, the in vivo functions of FOXR2 remain elusive. METHODS:We analyzed the effect of Foxr2 overexpression in the mouse brain by generating a transgenic strain that expresses Foxr2 in the entire brain under the Trp53 deficient background. We performed histological analysis of tumors and characterized tumor-derived sphere-forming cells. We investigated gene expression profiles of tumor-derived cells. RESULTS:Foxr2 and Trp53 loss promoted tumor formation in the olfactory bulb (OB) and brainstem (BS). The tumors showed the common morphological features of small round blue cell tumors, exhibiting divergent, mainly neuronal and glial, patterns of differentiation, which corresponds to the definition of CNS-embryonal tumors. Importantly, all mice developed CNS-embryonal tumors. In the OB, early proliferative lesions consisting of Olig2+ cells were observed, indicating that Foxr2 expression expanded Olig2+ cells in the OB. Tumor-derived cells formed spheres in vitro and induced tumors that recapitulated the parental tumor upon transplantation, indicating the presence of tumor-initiating cells. Gene expression profiling revealed that OB and BS tumor cells were enriched for the expression of the genes specific to CNS NB-FOXR2. CONCLUSIONS:Our data demonstrate that Foxr2 plays a causative role in the formation of CNS-embryonal tumors.
| S-EPMC6682215 | biostudies-literature
Project description:Central nervous system (CNS) embryonal tumors are a heterogeneous group of high-grade malignancies, and the increasing clinical use of methylation profiling and next-generation sequencing has led to the identification of molecularly distinct subtypes. One proposed tumor type, CNS tumor with BRD4::LEUTX fusion, has been described. As only a few CNS tumors with BRD4::LEUTX fusions have been described, we herein characterize a cohort of 9 such cases (4 new, 5 previously published) to further describe their clinicopathologic and molecular features. We demonstrate that CNS embryonal tumor with BRD4::LEUTX fusion comprises a well-defined methylation class/cluster. We find that patients are young (4 years or younger), with large tumors at variable locations, and frequently with evidence of leptomeningeal/cerebrospinal fluid (CSF) dissemination. Histologically, tumors were highly cellular with high-grade embryonal features. Immunohistochemically, 5/5 cases showed synaptophysin and 4/5 showed OLIG2 expression, thus overlapping with CNS neuroblastoma, FOXR2-activated. DNA copy number profiles were generally flat; however, two tumors had chromosome 1q gains. No recurring genomic changes, besides the presence of the fusion, were found. The LEUTX portion of the fusion transcript was constant in all cases assessed, while the BRD4 portion varied but included a domain with proto-oncogenic activity in all cases. Two patients with clinical follow up available had tumors with excellent response to chemotherapy. Two of our patients were alive without evidence of recurrence or progression after gross total resection and chemotherapy at 16 and 33 months. One patient relapsed, and the last of our four patients died of disease one month after diagnosis. Overall, this case series provides additional evidence for this as a distinct tumor type defined by the presence of a specific fusion as well as a distinct DNA methylation signature. Studies on larger series are required to further characterize these tumors.
| S-EPMC10946093 | biostudies-literature
Project description:Central nervous system primitive neuroectodermal tumors (CNS PNET) and medulloblastomas are both embryonal tumors that predominantly occur in children. We used microarrays to analyse a cohort of CNS PNETs and medulloblastomas to identify gene expression related to tumor subgroups. RNA extracted from 23 frozen tumor samples, plus a commercial fetal brain sample, was analysed using Affymetrix U133 plus 2.0 arrays. Tumour subgroups, based on gene expression, were identified using clustering methods.
2013-05-01 | E-GEOD-19404 | biostudies-arrayexpress
Project description:A bright side of Zika: potent and selective oncolytic properties against aggressive human CNS embryonal tumors
| PRJNA407687 | ENA
Project description:Embryonal tumors with multilayered rosettes (ETMR) are rare malignant embryonal brain tumors. The prognosis of ETMR is poor and novel therapeutic approaches are desperately needed. Comprehension of ETMR tumor biology is based on only few previous molecular studies, which mainly relied on the analyses of nucleic acids. In this study, we explored integrated ETMR proteomics with the aim to identify novel therapeutic vulnerabilities in these deadly tumors. Using mass spectrometry, proteome data were acquired from FFPE tissue of 40 embryonal brain tumors (16 ETMR, 9 atypical teratoid/rhabdoid tumors (AT/RT), 15 medulloblastomas (MB)) and integrated with case-matched global DNA methylation data, publicly available transcriptome data, and proteome data of further pediatric brain tumors. Proteome-based cluster analyses grouped ETMR samples according to histomorphology, separating neuropil-rich tumors with neuronal signatures from primitive tumors with signatures relating to stemness and chromosome organization. Microdissection analyses highlighted the close relationship of ETMR histomorphology and proteome profiles, regardless of intra- or intertumoral comparisons. Integrated proteomics showcased that ETMR harbor proteasome regulatory proteins in abundancy, implicating their strong dependency on the proteasome machinery to safeguard proteostasis. Respectively, in vitro cell culture viability assays using embryonal brain tumor cell lines BT183 (ETMR), BT16 (AT/RT), and D283 (MB) highlighted that ETMR cells were highly vulnerable towards treatment with the CNS penetrant proteasome inhibitor Marizomib. In summary, histomorphology stipulates the proteome signatures of ETMR. Pervasive and histomorphology-independent abundancy of proteasome regulatory proteins in ETMR indicates a strong proteasome dependency throughout these tumors. As validated in cell culture experiments, proteasome inhibition poses a promising therapeutic option in ETMR.
2024-01-08 | PXD045268 | Pride