Transcriptome Sequencing of Pediatric Neuroblastoma
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ABSTRACT: Neuroblastoma is the most common extra-cranial solid tumor in children. It represents 8% to 10% of all childhood cancers. Stage 4 Neuroblastoma is characterized by its clinical heterogeneous outcome. The special category, stage 4S tumors (2-5% of all NB) are chemo-sensitive, and the patients show spontaneous regression. On the other hand, MYCN amplification (25-30% of all NB) is associated with poor outcome of neuroblastoma, thus we further categorize stage 4 neuroblastoma into MYCN non-amplified and MYCN amplified group. Here we use transcriptome sequencing to characterize the transcriptome in 29 stage 4 Neuroblastoma samples.
SECONDARY ACCESSION(S): PRJNA275174PRJNA275173
REPOSITORIES: dbGaP
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Project description:Neuroblastoma (NB) is the most common extra cranial solid tumor in infants. Although several risk factors including patient age, disease stage and genetic abnormalities, such as MYCN amplification and 11q deletion, have been shown to predict outcome, the mechanisms responsible for the heterogeneous clinical behavior of this tumor, ranging from spontaneous regression to rapid progression of disease and patient’s death, remain largely unknown. Patients with disseminated disease mainly show metastasis at bone marrow (BM) and bone. The presence of metastasis is an independent unfavorable prognostic factor for NB patients over 18 months of age at diagnosis, whose event-free and overall survivals are grim despite intensive multimodal therapies. We decided to investigate the transcriptome of both NB metastatic cells and resident hematopoietic BM cells to get insight on potential targets for diagnostic, prognostic and therapeutic purposes. Hereby, we report on the results obtained by comparing BM resident hematopoietic cells in the presence and absence of infiltrating NB hematopoietic cells with BM cells from young healthy donors. We analyzed gene expression profiles of 40 bone marrow samples: 8 from healthy young donor; 23 from NB patients with stage 1, 2, 3; 9 from NB patients with stage 4.
2011-09-29 | E-GEOD-25624 | biostudies-arrayexpress
Project description:Dedifferentiated liposarcoma (DDLPS) is an aggressive mesenchymal cancer marked by amplification of MDM2, an inhibitor of the tumor suppressor TP53. DDLPS patients with higher MDM2 amplification have lower chemotherapy sensitivity and worse outcome than patients with lower MDM2 amplification. We hypothesized that MDM2 amplification levels may be associated with changes in DDLPS metabolism. Six patient-derived DDLPS cell line models were subject to comprehensive metabolomic (Metabolon) and lipidomic (SCIEX 5600 TripleTOF-MS) profiling to assess associations with MDM2 amplification and their responses to metabolic perturbations. Comparing metabolomic profiles between MDM2 higher and lower amplification cells yielded a total of 23 differentially abundant metabolites across both panels (FDR < 0.05, log2 FC < 0.75), including ceramides, glycosylated ceramides, and sphingomyelins. Disruption of lipid metabolism through statin administration resulted in a chemo-sensitive phenotype in MDM2 lower cell lines only, suggesting that lipid metabolism may be a large contributor to the more aggressive nature of MDM2 higher DDLPS tumors. This study is the first to provide comprehensive metabolomic and lipidomic characterization of DDLPS cell lines and provides evidence for MDM2-dependent differential molecular mechanisms that are critical factors in chemoresistance and could thus affect patient outcome.
2020-05-22 | ST001405 | MetabolomicsWorkbench
Project description:Neuroblastoma (NB) is the most common extra cranial solid tumor in infants. Although several risk factors including patient age, disease stage and genetic abnormalities, such as MYCN amplification and 11q deletion, have been shown to predict outcome, the mechanisms responsible for the heterogeneous clinical behavior of this tumor, ranging from spontaneous regression to rapid progression of disease and patient’s death, remain largely unknown. Patients with disseminated disease mainly show metastasis at bone marrow (BM) and bone. The presence of metastasis is an independent unfavorable prognostic factor for NB patients over 18 months of age at diagnosis, whose event-free and overall survivals are grim despite intensive multimodal therapies. We decided to investigate the transcriptome of both NB metastatic cells and resident hematopoietic BM cells to get insight on potential targets for diagnostic, prognostic and therapeutic purposes. Hereby, we report on the results obtained by comparing BM resident hematopoietic cells in the presence and absence of infiltrating NB hematopoietic cells with BM cells from young healthy donors.
2011-09-30 | GSE25624 | GEO
Project description:Neurotrophic receptor tyrosine kinases, also known as Tropomyosin receptor kinases (TrkA, TrkB and TrkC), despite their homology, contribute to the clinical heterogeneity of childhood cancer neuroblastoma. TrkA expression is associated with low-stage disease and is often seen with spontaneous tumour regression. Conversely, TrkB is present in unfavourable neuroblastomas that often harbour amplification of the MYCN oncogene. The role of TrkC is less clearly defined, although some studies suggest its association with a favourable outcome. Understanding the differences in the activity of Trk receptors that drive divergent clinical phenotypes as well as the influence of MYCN amplification on downstream Trk receptor signalling remain poorly understood. Here, we present a comprehensive label-free mass spectrometry-based total proteomics and phosphoproteomics dataset where we identified and quantified 4,907 proteins, 16,744 phosphosites and 5,084 phosphoproteins, derived from NGF/BDNF/NT-3 treated TrkA/B/C-overexpressing neuroblastoma cells with differential MYCN status. Analysing our dataset offers valuable insights into TrkA/B/C receptor signalling in neuroblastoma and its modulation by MYCN status; and holds potential for advancing therapeutic strategies in this challenging childhood cancer.
2024-08-29 | PXD054441 | Pride
Project description:The goal of this study is to identify circulating microRNAs with prognostic value in a large cohort of comatose survivors of out-of-hospital cardiac arrest. We performed RNA-Seq for short RNAs in plasma, collected 48 hours after return of spontaneous circulation, of 50 cardiac arrest patients including 25 good neurological outcome at 6 months (cerebral performance category 1) and 25 poor neurological outcome including death at 6 months (cerebral performance category score 5). The sequencing generated on average 18.5 million reads per sample. After mapping the reads and counting to relevant entries in miRBase 20, we found 236 microRNAs detected in all 50 samples with TPM above or equals to 1. 11 microRNAs were differentially expressed between 2 groups with False Discovery Rate (FDR) < 5%.
2020-07-15 | GSE74198 | GEO
Project description:MYCN amplification in neuroblastoma leads to aberrant expression of MYCN oncoprotein, which binds active genes promoting transcriptional amplification. Yet how MYCN coordinates transcription elongation to meet productive transcriptional amplification and which elongation machinery represents MYCN-driven vulnerability remain to be identified. We conducted a targeted screen of transcription elongation factors and identified the super elongation complex (SEC) as a unique vulnerability in MYCN-amplified neuroblastomas. MYCN directly binds EAF1 and recruits SEC to enhance processive transcription elongation. Depletion of EAF1 or AFF1/AFF4, another core subunit of SEC, leads to a global reduction in transcription elongation and elicits selective apoptosis of MYCN-amplified neuroblastoma cells. A combination screen reveals SEC inhibition synergistically potentiates the therapeutic efficacies of FDA-approved BCL2 antagonist ABT-199, in part due to suppression of MCL1 expression, both in MYCN-amplified neuroblastoma cells and in patient-derived xenografts. These findings identify disruption of the MYCN-SEC regulatory axis as a promising therapeutic strategy in neuroblastoma.
2023-05-10 | PXD039332 | Pride
Project description:The stabilization of MYCN by FOXR2 represents an alternative mechanism to MYCN amplification to increase MYCN protein levels. As such, FOXR2 expression identifies another subset of neuroblastoma patients with unfavorable clinical outcome. Background: Clinical outcomes of neuroblastoma patients range from spontaneous tumor regression to fatality. Hence, understanding the mechanisms that cause tumor progression are crucial for the treatment of patients. In this study, we show that FOXR2 activation identifies a subset of neuroblastoma tumors with unfavorable outcome and we investigate the mechanism how FOXR2 relates to poor outcome in patients.
2021-10-13 | GSE156092 | GEO
Project description:There will be three parts to this phase I study: 1) the Combination Dose Finding cohort; 2) the Combination Expansion cohort; and 3) the Monotherapy MET Amplified cohort. In the Combination Dose Finding cohort and the Combination Expansion cohort, we will combine cabozantinib and panitumumab in patients with KRAS wild-type metastatic colorectal cancer (CRC). In the Monotherapy MET Amplified cohort, we will screen at least 50 patients for MET gene amplification ("MET amplification"). Patients with MET amplification will receive cabozantinib only (monotherapy).
The primary objective of this open-label phase Ib trial are:
1. To determine the maximum tolerated dose and the recommended phase II dose for the combination of cabozantinib and panitumumab in patients with KRAS wild-type metastatic colorectal cancer and
2. To identify the objective response rate (ORR) of cabozantinib monotherapy in patients with prospectively identified MET amplified metastatic colorectal cancer.
The secondary objectives are:
1. To describe the non-dose limiting toxicities of cabozantinib and panitumumab.
2. To describe the clinical activity (ORR, PFS, OS) of cabozantinib and panitumumab.
3. To describe the safety and tolerability of cabozantinib monotherapy in patients with MET amplified colorectal cancer.
4. To describe the clinical activity (PFS, OS) of cabozantinib monotherapy in patients with MET amplified colorectal cancer.
| 2156647 | ecrin-mdr-crc
Project description:Here we modified a single cell whole transcriptome amplification method to make it capable of amplifying cDNAs as long as 3kb efficiently and unbiasedly. We combined this modified single cell cDNA amplification method with Applied Biosystems next generation sequencing SOLiD™ System to set up a single cell whole transcriptome assay. The modified amplification strategy allows us to amplify full-length cDNAs for most of the expressed genes. We show that it is feasible to get digital gene expression profiles at single cell resolution. This allows us to ask fundamental biological questions that could not be addressed previously and to understand transcriptome complexity at the resolution of a single cell. Oocyte, Two-cell, Four-cell, and 8-cell stage embryos were recovered from MF1 females mated with MF1 male mice (Nagy et al. 2003). The zona pellucida was removed by treatment with acidic tyrode solution. The individual blastomeres were separated by gentle pipeting using a glass capillary.
2010-12-31 | GSE22182 | GEO
Project description:Simple Summary: Neuroblastoma (NB) accounts for 15% of all cancer related deaths of children. While amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB, expression of the neurotrophin receptor, NTRK1/TrkA, has been shown to associate with an excellent outcome. MYCN down-regulates NTRK1 expression, but it is unknown if the molecular effects of NTRK1 signaling also affect MYCN-induced networks. The aim of this study was to decipher NTRK1 signaling using an unbiased proteome and phosphoproteome approach. To this end, we realized inducible ectopic NTRK1-expression in a NB cell line with MYCN amplification and analyzed the proteomic changes upon NTRK1-activation in a time-dependent manner. In line with phenotypes observed, NTRK1-activation induced markers of neuronal differentiation and cell cycle arrest. Most prominently, NTRK1 upregulated expression and phosphorylation of the nuclear lamina component Lamin A/C. Moreover, NTRK1 signaling also induced aggregation of LMNA within nucleic foci, which accompanies differentiation in other cell types. Abstract: Background: Neuroblastomas (NB) are the most common extracranial solid tumors of childhood. Amplification of the Myc-N proto-oncogene (MYCN) is a major driver of NB aggressiveness, while high expression of the neurotrophin receptor NTRK1/TrkA is associated with mild disease courses. The molecular effects of NTRK1 signaling in MYCN-amplified NB, however, are still poorly understood and require elucidation. Methods: Inducible NTRK1-expression was realized in four NB cell lines with (IMR5, NGP) or without MYCN amplification (SKNAS, SH-SY5Y). Proteome and phosphoproteome dynamics upon NTRK1-activation by its ligand, NGF, were analyzed in a time-dependent manner in IMR5 cells. Target validation by immunofluorescence staining and automated image processing was performed using the three other NB cell lines. Results: In total, 230 proteins and 134 single phosphorylated class I phosphosites were found to be significantly regulated upon NTRK1 activation. Among known NTRK1-targets, Stathmin and the neurosecretory protein VGF were recovered. Additionally, we observed upregulation and phosphorylation of Lamin A/C (LMNA) that accumulated inside nuclear foci. Conclusions: We provide a comprehensive picture of NTRK1-induced proteome and phosphoproteome dynamics. Phosphorylation of LMNA within nucleic aggregates was identified as a prominent feature of NTRK1 signaling independent of the MYCN status of NB cells.
2021-11-11 | PXD026913 | Pride