Genomic profiles of unresectable localized peripheral neuroblastic tumours without MYCN amplificatioun of children over the age of 12 months
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PROVIDER: PRJNA443147 | ENA |
REPOSITORIES: ENA
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Project description:Background: The prognostic impact of segmental chromosome alterations (SCAs) in children older than 1 year, diagnosed with localised unresectable neuroblastoma (NB) without MYCN amplification enrolled in the European Unresectable Neuroblastoma (EUNB) protocol is still to be clarified, while, for other group of patients, the presence of SCAs is associated with poor prognosis. Methods: To understand the role of SCAs we performed multilocus/pangenomic analysis of 98 tumour samples from patients enrolled in the EUNB protocol. Results: Age at diagnosis was categorised into two groups using 18 months as the age cutoff. Significant difference in thepresence of SCAs was seen in tumours of patients between 12 and 18 months and over 18 months of age at diagnosis, respectively (P<0.04). A significant correlation (P<0.03) was observed between number of SCAs per tumour and age. Event-free (EFS) andoverall survival (OS) were calculated in both age groups, according to both the presence and number of SCAs. In older patients, a poorer survival was associated with the presence of SCAs (EFS<46% vs 75%, P<0.023; OS<66.8% vs 100%, P<0.003). Moreover, OS of older patients inversely correlated with number of SCAs (P<0.002). Finally, SCAs provided additional prognostic information beyond histoprognosis, as their presence was associated with poorer OS in patients over 18 months with unfavourable International Neuroblastoma Pathology Classification (INPC) histopathology (P<0.018). Conclusions: The presence of SCAs is a negative prognostic marker that impairs outcome of patients over the age of 18 months with localised unresectable NB without MYCN amplification, especially when more than one SCA is present. Moreover, in older patients with unfavourable INPC tumour histoprognosis, the presence of SCAs significantly affects OS.
2018-03-22 | GSE112173 | GEO
Project description:Gene expression analysis of Th-MYCN neuroblastoma tumours treated with CBL0137 and panobinostat
| PRJNA636966 | ENA
Project description:This series represents the data set described in the publication “Genetic and Immunohistochemical Analysis of Localized Extranodal and Nodal Dendritic Cell Tumours – An Outlook for Individualized Therapies in Rare Tumours” by Ullmann et al. (submitted). Keywords: array CGH
2007-03-15 | GSE4838 | GEO
Project description:To evaluate the expression of genes associated with MYCN in NB, 10 tumors with MYCN amplification and 10 with normal MYCN copy number were subjected to oligonucleotide microarray using Agilent oligo microarray chips. Two-condition experiment, MYCN normal vs. MYCN amplified 10 NB patient tissues for each group.
2013-12-17 | E-GEOD-53371 | biostudies-arrayexpress
Project description:The MYCN oncoprotein forms a DNA-binding heterodimer with its partner protein MAX. MYCN-driven tumor cells depend on the nuclear exosome, a 3`-5` RNA exonuclease complex, to progress through S phase. Here we show that MYCN forms stable high molecular weight complexes with the nuclear exosome and additional RNA-binding proteins. Enhanced cross-linking and immunoprecipitation (eCLIP) experiments reveal that MYCN binds to thousands of sites on RNA, mainly localized in introns. MYCN directly binds RNA with a preference for UG-rich sequences via a short, highly conserved sequence motif termed MycBox I. Upon exosome inhibition, MYCN relocalizes globally from promoters to intronic RNAs; at promoters, MYCN is then replaced by the repressive MXD6 (MNT) protein, leading to the recruitment of histone deacetylase complexes and inhibition of MYCN-dependent transcription. MYCN is tightly associated with the exosome targeting complex NEXT and promotes the degradation of non-polyadenylated RNA at its bound introns. Our data demonstrate that MYCN is an RNA-binding protein that controls nascent RNA turnover and argue that the competition between RNA- and DNA-bound states of MYCN links the dynamics of the MYCN/MAX/MXD network to the completion of mRNA processing.
2024-07-18 | PXD044446 | Pride
Project description:Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
2017-01-10 | GSE84042 | GEO
Project description:Prostate tumours are highly variable in their response to therapies, but clinically available prognostic factors can explain only a fraction of this heterogeneity. Here we analysed 200 whole-genome sequences and 277 additional whole-exome sequences from localized, non-indolent prostate tumours with similar clinical risk profiles, and carried out RNA and methylation analyses in a subset. These tumours had a paucity of clinically actionable single nucleotide variants, unlike those seen in metastatic disease. Rather, a significant proportion of tumours harboured recurrent non-coding aberrations, large-scale genomic rearrangements, and alterations in which an inversion repressed transcription within its boundaries. Local hypermutation events were frequent, and correlated with specific genomic profiles. Numerous molecular aberrations were prognostic for disease recurrence, including several DNA methylation events, and a signature comprised of these aberrations outperformed well-described prognostic biomarkers. We suggest that intensified treatment of genomically aggressive localized prostate cancer may improve cure rates.
2017-01-10 | GSE83917 | GEO
Project description:Here we sought metabolic alterations specifically associated with amplified MYCN as nodes to indirectly target the MYCN oncogene. Liquid chromatography-mass spectrometry-based proteomics identified 7 proteins consistently correlated with MYCN in proteomes from 49 neuroblastoma biopsies and 13 cell lines. Among these were phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme in de novo serine synthesis. MYCN associated with two regions in the PHGDH promoter, supporting transcriptional PHGDH regulation by MYCN. Pulsed stable isotope-resolved metabolomics utilizing 13C-glucose labeling demonstrated higher de novo serine synthesis in MYCN-amplified cells compared to cells with diploid MYCN. An independence of MYCN-amplified cells from exogenous serine and glycine was demonstrated by serine and glycine starvation, which attenuated nucleotide pools and proliferation only in cells with diploid MYCN but did not diminish these endpoints in MYCN-amplified cells. Proliferation was attenuated in MYCN-amplified cells by CRISPR/Cas9-mediated PHGDH knockout or treatment with PHGDH small molecule inhibitors without affecting cell viability. PHGDH inhibitors administered as single-agent therapy to NMRI-Foxn1nu/nu mice harboring patient-derived MYCN-amplified neuroblastoma xenografts slowed tumor growth. However, combining a PHGDH inhibitor with the standard-of-care chemotherapy drug, cisplatin, revealed antagonism of chemotherapy efficacy in vivo. Emergence of chemotherapy resistance was confirmed in the genetic PHGDH knockout model in vitro. Altogether, PHDGH knockout and inhibition by small molecules consistently slows proliferation, but stops short of killing the cells, which then establish resistance to classical chemotherapy. Although PHGDH inhibition with small molecules has produced encouraging results in other preclinical cancer models, this approach must be considered with caution in patients with neuroblastoma.
2020-12-11 | PXD018300 | Pride
Project description:MYCN amplification (MNA) is a defining feature of high-risk neuroblastoma (NB) that predicts poor prognosis. However, whether genes within or in close proximity to the MYCN amplicon also contribute to aggressiveness in MNA+ NB remains poorly understood. Here we identify that GREB1, a transcription factor encoding gene neighboring the MYCN locus, is frequently co-expressed with MYCN, and promotes cell survival in MNA+ NB. GREB1 controls gene expression independently of MYCN in MNA+ NB, among which we uncover Myosin 1B (MYO1B) as being highly expressed in MNA+ NB. MYO1B promotes aggressive features, including invasive capacity in vitro, as well as extravasation and distant metastasis in vivo. Global secretome and proteome profiling further delineate MYO1B as a major regulator of secretome reprogramming in MNA+ NB cells. Moreover, we identify the cytokine MIF as an important pro-invasive and pro-metastatic mediator of MYO1B activity. Together, we have identified a putative GREB1-MYO1B-MIF axis as an unconventional mechanism that promotes the aggressiveness of MNA+ NB, and independently of MYCN. Furthermore, we find that MYO1B is upregulated in association with other oncoproteins during cellular transformation, and is dramatically increased in multiple human cancer types, suggesting a crucial role of MYO1B in cancers in addition to MNA+ NB.
2023-10-24 | PXD039410 | Pride
Project description:Group 3 medulloblastoma (MB) carries the worst prognosis of the four molecular subgroups of MB. MYC amplifications represent the most common genetic alteration in Group 3 MB. By specifically driving MYC in hindbrain cells using a Tet-OFF system, we established a novel murine model of MB (GMYC) that accurately recapitulates human Group 3 MB. GMYC tumours develop with 60-70% penetrance, without p53 mutations, and are monoclonal as revealed by multicolour cell fate tracing. Compared to MYCN-driven Group 3 tumours driven from the same promoter, the ARF suppressor gene was significantly downregulated in GMYC tumours and specifically silenced by methylation in MYC-amplified human MB. While MYCN-driven tumour malignancy was more sensitive to ARF depletion, it dramatically increased the metastatic spread of MYC-driven tumours. Finally, the DNMT inhibitor decitabine could restore ARF levels and suppress MYC-driven tumour growth providing a promising targeting approach for these high-risk tumours.
2022-12-21 | GSE139240 | GEO