Classification of neuroblastoma by integrating gene expression pattern with regional alterations in DNA copy number
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE3960 | GEO | 2006/01/04
SECONDARY ACCESSION(S): PRJNA94217
REPOSITORIES: GEO
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Project description:The specific genes that influence neuroblastoma biology and are targeted by genomic alterations remain largely unknown. We quantified mRNA expression in a highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors and the expression profiles were determined using Affymetrix U95Av2 arrays. Comparisons between the sample groups allow the identification of genes with localized expression patterns. This study demonstrates that the genomic data can be used to subcategorize the disease into molecular subsets and the regional copy number alterations are correlated with a broad number of transcriptional alterations genome wide. This data also suggests that multiple genes from several discrete regions of the human genome co-operate to supress neuroblastoma tumorigenesis and progression. Experiment Overall Design: A highly annotated series of 101 prospectively collected diagnostic neuroblastoma primary tumors were selected to quantify mRNA expression using an oligonucleotide based microarray. Genomic copy number status at the prognostically relevant loci 1p36,2p24(MYCN), 11q23 and 17q23 was determined by PCR and was aberrant in 26, 20, 40 and 38 cases, respectively. Fetal brain RNA was used as a control sample.
2008-06-12 | E-GEOD-3960 | biostudies-arrayexpress
Project description:Gene expression analysis was performed on 30 Neuroblastomas to identify genes whose transcription is significantly altered by recurrent chromosomal alterations. Genomic copy number losses and gains had been delineated in the tumours using FISH and SNP arrays. We have identified genes significantly altered by 7 recurrent alterations: 1p, 3p, 4p, 10q and 11q loss, 2p and 17q gain, and genes co-amplified and over-expressed as a result of MYCN amplification. Identifying genes whose expression is consistently altered by chromosomal gains or losses is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastoma, where multiple genomic copy number changes of proven prognostic value exist. We have used Affymetrix microarrays and a combination of fluorescent in-situ hybridisation and single nucleotide polymorphism (SNP) microarrays to establish expression profiles and delineate copy number alterations in 30 primary neuroblastomas. Experiment Overall Design: 30 neuroblastomas were obtained from patients of all stages (10 patients - stage 1, 2, 3 or 4s disease, 20 patients - stage 4 disease). RNA samples were extracted and analysed using Affymetrix Human Genome U133 Plus 2.0 Arrays. Patient were treated according to the United Kingdom Childrenâs Cancer Study Group [UKCCSG], European Neuroblastoma Study Group and Localised Neuroblastoma European Study Group protocols.
2008-10-26 | E-GEOD-13136 | biostudies-arrayexpress
Project description:We conducted a prospective monocenter clinical trial called PERMED01 to evaluate the number patients with locally advanced or metastatic cancer for whom identification of molecular alterations in tumor samples could lead to the delivery of a targeted therapy. Patients accessible to tumor biopsy were prospectively enrolled at the Paoli-Calmettes Institute in the PERMED01 study (ClinicalTrials.gov, NCT02342158). Genomic profiling of frozen tissue was established by whole-genome array comparative genomic hybridization (aCGH)
2021-03-01 | E-MTAB-9998 | biostudies-arrayexpress
Project description:Gene expression analysis was performed on 30 Neuroblastomas to identify genes whose transcription is significantly altered by recurrent chromosomal alterations. Genomic copy number losses and gains had been delineated in the tumours using FISH and SNP arrays. We have identified genes significantly altered by 7 recurrent alterations: 1p, 3p, 4p, 10q and 11q loss, 2p and 17q gain, and genes co-amplified and over-expressed as a result of MYCN amplification. Subsequently, correlation of microarray data with survival and expression within rodent neuroblastomas were used to identify genes likely to be involved in the disease progression, and identified a significant excess of differentially expressed genes which correlated with survival within the minimally altered regions on 17q and 4p; Identifying genes whose expression is consistently altered by chromosomal gains or losses is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastoma, where multiple genomic copy number changes of proven prognostic value exist. We have used Affymetrix microarrays and a combination of fluorescent in-situ hybridisation and single nucleotide polymorphism (SNP) microarrays to establish expression profiles and delineate copy number alterations in 30 primary neuroblastomas. Correlation of microarray data with patient survival and analysis of expression within rodent neuroblastoma cell lines were then used to further define genes likely to be involved in the disease process. Using this approach we identify >1000 genes within 8 recurrent genomic alterations (loss of 1p, 3p, 4p, 10q and 11q, 2p gain, 17q gain, and the MYCN amplicon) whose expression is consistently altered by copy number change. Of these, 84 correlate with patient survival, with the minimal regions of 17q gain and 4p loss being significantly enriched for such genes. Orthologues of all but one of these genes on 17q are overexpressed in rodent neuroblastoma cell lines. A significant excess of SNPs whose copy number correlates with survival is also observed on proximal 4p in stage 4 tumours, and we find that deletion of 4p is associated with improved outcome in an extended cohort of tumours. These results define the major impact of genomic copy number alterations upon transcription within neuroblastoma, and highlight genes on distal 17q and proximal 4p for downstream analyses. They also suggest that integration of discriminators such as survival and comparative gene expression with microarray data may be useful in the identification of critical genes within regions of loss or gain in many human cancers. Experiment Overall Design: Chromosomal gains and losses were delineated in Stage 4 neuroblastomas to facilitate, in combination with expression array data, the identification of genes within regions of gain and loss whose expression is significantly altered by copy number change.
2008-10-26 | E-GEOD-13137 | biostudies-arrayexpress
Project description:Microarray-based genome-wide measurements of copy number alterations and of transcriptome variations are proposed for neuroblastoma prognosis and possible treatment choice. Nonetheless, they lack to provide clues on a neglected layer of systems-level changes, the translatome, whose variations are defined by the activity of the translational regulatory machinery. Our study extends the conventional genome-wide approaches to translatome profiling in neuroblastoma, by means of polysomal sucrose gradient separation followed by microarray analysis. The panel of fourteen parental (not subcloned) neuroblastoma cell lines used in the study includes: CHP-134, SIMA, NB-69, LAN-1, KELLY, CHP-126, CHP-212, SK-N-BE(2), IMR-32, SK-N-AS, SK-N-SH, STA-NB-7, STA-NB-1, STA-NB-10 cells. Each cell line has been profiled with high resolution array CGH analysis for copy number changes, and for transcriptome and translatome variations. The integration of these three types of data sets obtained from the same cells can provide information on the impact in neuroblastoma of a defined pattern of genomic lesions on both transcriptional and translational alterations of gene expression.
2010-12-31 | GSE22785 | GEO
Project description:Gene expression analysis was performed on 30 Neuroblastomas to identify genes whose transcription is significantly altered by recurrent chromosomal alterations. Genomic copy number losses and gains had been delineated in the tumours using FISH and SNP arrays. We have identified genes significantly altered by 7 recurrent alterations: 1p, 3p, 4p, 10q and 11q loss, 2p and 17q gain, and genes co-amplified and over-expressed as a result of MYCN amplification. Subsequently, correlation of microarray data with survival and expression within rodent neuroblastomas were used to identify genes likely to be involved in the disease progression, and identified a significant excess of differentially expressed genes which correlated with survival within the minimally altered regions on 17q and 4p Identifying genes whose expression is consistently altered by chromosomal gains or losses is an important step in defining genes of biological relevance in a wide variety of tumour types. However, additional criteria are needed to discriminate further among the large number of candidate genes identified. This is particularly true for neuroblastoma, where multiple genomic copy number changes of proven prognostic value exist. We have used Affymetrix microarrays and a combination of fluorescent in-situ hybridisation and single nucleotide polymorphism (SNP) microarrays to establish expression profiles and delineate copy number alterations in 30 primary neuroblastomas. Correlation of microarray data with patient survival and analysis of expression within rodent neuroblastoma cell lines were then used to further define genes likely to be involved in the disease process. Using this approach we identify >1000 genes within 8 recurrent genomic alterations (loss of 1p, 3p, 4p, 10q and 11q, 2p gain, 17q gain, and the MYCN amplicon) whose expression is consistently altered by copy number change. Of these, 84 correlate with patient survival, with the minimal regions of 17q gain and 4p loss being significantly enriched for such genes. Orthologues of all but one of these genes on 17q are overexpressed in rodent neuroblastoma cell lines. A significant excess of SNPs whose copy number correlates with survival is also observed on proximal 4p in stage 4 tumours, and we find that deletion of 4p is associated with improved outcome in an extended cohort of tumours. These results define the major impact of genomic copy number alterations upon transcription within neuroblastoma, and highlight genes on distal 17q and proximal 4p for downstream analyses. They also suggest that integration of discriminators such as survival and comparative gene expression with microarray data may be useful in the identification of critical genes within regions of loss or gain in many human cancers. Keywords: Disease State Analysis
2008-10-09 | GSE13137 | GEO
Project description:Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCN-WT TERT-WT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.
2018-10-25 | GSE120559 | GEO
Project description:Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations that may contribute to their heterogeneous behavior. However, their clinical relevance and potential interest in identifying appropriate candidate drugs for personalized management are not well known. In this study, targeted next generation sequencing and genomic copy number alterations (CNA) were analyzed in 150 cases of diffuse large B-cell lymphoma (DLBCL) to define the clinical significance of recurrent genomic alterations and to identify potential targets for personalized management. An independent cohort of 111 patients was also analyzed to confirm the clinically significant findings. We found a differential profile of mutations, altered pathogenic pathways and CNA in germinal center B (GCB) and activated B-cell (ABC)-DLBCL with some shared alterations in both subtypes. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis that was independent of other parameters and confirmed in the validation cohort. Tumors with NOTCH pathway mutations had a significant overexpression of downstream target genes, emphasizing the relevance of this pathway in DLBCL. We identified other new relevant genes including TMEM30A, RHOA, EBF, and TOX, among others. In silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials (n=66) or pre-clinical assays (n=3) in DLBCL or other lymphomas. These findings orient future preclinical and clinical intervention strategies in DLBCL.
2018-03-14 | GSE94705 | GEO
Project description:Our study proposes a precise mechanistic classification of clinical neuroblastoma phenotypes that is based on telomere maintenance mechanisms and RAS or p53 pathway mutations. A crucial factor in telomere maintenance is overexpression of TERT. We therefore determined a TERT expression threshold to identify MYCNWT TERTWT tumors whose TERT mRNA levels are comparable to those of tumors bearing MYCN or TERT alterations.
2018-10-25 | GSE120568 | GEO
Project description:Title: Array-based gene expression, CGH and tissue data define a 12q24 gain in neuroblastic tumors with prognostic implication. Background: Neuroblastoma has successfully served as a model system for the identification of neuroectoderm-derived oncogenes. However, in spite of various efforts, only a few clinically useful prognostic markers have been found. Here, we present a framework, which integrates DNA, RNA and tissue data to identify and prioritize genetic events that represent clinically relevant new therapeutic targets and prognostic biomarkers for neuroblastoma. Methods: A single-gene resolution aCGH profiling was integrated with microarray-based gene expression profiling data to distinguish genetic copy number alterations that were strongly associated with transcriptional changes in two neuroblastoma cell lines. FISH analysis using a hotspot tumour tissue microarray of 37 paraffin-embedded neuroblastoma samples and in silico data mining for gene expression information obtained from previously published studies including up to 445 healthy nervous system samples and 123 neuroblastoma samples were used to evaluate the clinical significance and transcriptional consequences of the detected alterations and to identify subsequently activated gene(s). Results: In addition to the anticipated high-level amplification and subsequent overexpression of MYCN, MEIS1, CDK4 and MDM2 oncogenes, the aCGH analysis revealed numerous other genetic alterations, including microamplifications at 2p and 12q24.11. Most interestingly, we identified and investigated the clinical relevance of a previously poorly characterized amplicon at 12q24.31. FISH analysis showed low-level gain of 12q24.31 in 14 of 33 (42%) neuroblastomas. Patients with the low-level gain had an intermediate prognosis in comparison to patients with MYCN amplification (poor prognosis) and to those with no MYCN amplification or 12q24.31 gain (good prognosis) (P = 0.001). Using the in silico data mining approach, we identified elevated expression of five genes located at the 12q24.31 amplicon in neuroblastoma (DIABLO, ZCCHC8, RSRC2, KNTC1 and MPHOSPH9). Among these, DIABLO showed the strongest activation suggesting a putative role in neuroblastoma progression. Conclusions: The presented systematic and rapid framework, which integrates aCGH, gene expression and tissue data to obtain novel targets and biomarkers for cancer, identified a low-level gain of the 12q24.31 as a potential new biomarker for neuroblastoma progression. Furthermore, results of in silico data mining suggest a new neuroblastoma target gene, DIABLO, within this region, whose functional and therapeutic role remains to be elucidated in follow-up studies. High-resolution aCGH was utilized to identify novel genetic alterations in two neuroblastoma cell lines, NGP and IMR-32. Through the integration of gene copy number and gene expression data, the impact of copy number changes on expression levels was determined. Fluorescence in situ hybridization (FISH) on a tissue microarray (TMA) format was used to assess the clinical significance of the identified copy number increase at 12q24.31 in neuroblastoma patients. Finally, we used in silico data mining of publicly available transcriptomics data, to evaluate the transcriptional consequences of the detected 12q24.31 alteration and to identify subsequently activated gene(s). Here, aCGH of the NGP and IMR-32 cell lines was performed. Male genomic DNA was used as reference.
2010-05-05 | E-GEOD-18143 | biostudies-arrayexpress