Transcription profiling of human prognostic samples from neuroblastoma patients for classification of neuroblastoma by integrating gene expression pattern with regional alterations in DNA copy number
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Jayanti Jagannathan
PROVIDER: E-GEOD-3960 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Integrative genomics identifies distinct molecular classes of neuroblastoma and shows that multiple genes are targeted by regional alterations in DNA copy number.
Wang Qun Q Diskin Sharon S Rappaport Eric E Attiyeh Edward E Mosse Yael Y Shue Daniel D Seiser Eric E Jagannathan Jayanti J Shusterman Suzanne S Bansal Manisha M Khazi Deepa D Winter Cynthia C Okawa Erin E Grant Gregory G Cnaan Avital A Zhao Huaqing H Cheung Nai-Kong NK Gerald William W London Wendy W Matthay Katherine K KK Brodeur Garrett M GM Maris John M JM
Cancer research 20060601 12
Neuroblastoma is remarkable for its clinical heterogeneity and is characterized by genomic alterations that are strongly correlated with tumor behavior. 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 using an oligonucleotide-based microarray. Genomic copy number status at the prognostically relev ...[more]
Similar Datasets
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. Keywords: Disease state analysis, genetic modification
2006-01-04 | GSE3960 | 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. 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: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. 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: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: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. Keywords: Disease State Analysis
2008-10-09 | GSE13136 | GEO
Project description:<p>The Gabriella Miller Kids First Pediatric Research Program (Kids First) is a trans-NIH effort initiated in response to the 2014 Gabriella Miller Kids First Research Act and supported by the NIH Common Fund. This program focuses on gene discovery in pediatric cancers and structural birth defects and the development of the Gabriella Miller Kids First Pediatric Data Resource (Kids First Data Resource).</p> <p>All of the WGS and phenotypic data from this study are accessible through dbGaP and <a href="kidsfirstdrc.org" target="_blank">kidsfirstdrc.org</a>, where other Kids First datasets can also be accessed.</p> <p>Children with disseminated neuroblastoma have a very high risk of treatment failure and death despite receiving intensified chemotherapy, radiation therapy and immunotherapy. The <i>long-term goal</i> of our research program is to ultimately improve neuroblastoma cure rates by first comprehensively defining the genetic basis of the disease. The <i>central hypothesis</i> to be tested here is that neuroblastoma arises largely due to the epistatic interaction of common and rare heritable DNA variation. Here we will perform a comprehensive whole genome sequencing of 563 quartets of neuroblastoma patient germline and diagnostic tumor DNAs and germline DNAs from both parents. The case series was recently collected through a Children's Oncology Group epidemiology clinical trial and is robustly annotated with complete demographic (age, sex, race, ethnicity), clinical (e.g. age at diagnosis, stage, risk group), epidemiologic (parental dietary and exposure questionnaire) and biological (e.g. tumor <i>MYCN</i> status and multiple other tumor genomic measures) co-variates. Subjects were consented for genetic research and DNA is immediately available for shipment for sequencing. We propose Illumina-based whole genome sequencing in the 593 "trio" germline samples (<b>Aim 1</b>; due to missing parent: 487 full neuroblastoma triads, 106 child-single parent dyads = 1673 whole genome sequences) and matched diagnostic tumor DNA (<b>Aim 2</b>; N=366) at 30x sequencing depth (N=2039 whole genome sequences). Also in Aim 2 we will perform whole exome (100x) and RNA sequencing on the 366 tumor DNA and 228 tumor RNA samples from this cohort. Finally, we propose a pilot study of structural variation using long-range sequencing in 10 non-overlapping tumor samples chosen based on potentially relevant chromosomal alterations discovered with conventional NGS. Thus, a total of 2277 individual samples and 2655 sequences will be generated. We will use our established analytic pipeline that is currently being used to study the germline genomes of all cases sequenced through the NCI supported Therapeutically Applicable Research to Generate Effective Treatments program. We plan a three-stage analytic approach, first focusing on classic <i>de novo</i> and inherited Mendelian damaging alterations. We will next integrate our extensive epigenomic data from human neuroblastoma cell lines and genome-wide association study data (N=5,703 neuroblastoma cases to date) to guide a comprehensive assessment of noncoding variants that influence tumor initiation with a recently established analytic pipeline. Finally, we will utilize the tumor DNA analyses to inform relevance via somatic gain or loss of function effects at the sequence and/or copy number levels. All data generated in this project will be immediately placed into the Genomic Data Commons (GDC) and we will compute within this environment by importing our analytic pipelines into the GDC. These data will be fully integrated into the Kids First Data Resource and freely shared with all academically qualified petitioners. This comprehensive data set derived from a large and richly phenotyped series of neuroblastoma DNA quartets will be integrated with existing germline and/or tumor genomic data from over 6,000 neuroblastoma subjects (but none with matched patient-parent germline sequencing data) to provide an unparalleled opportunity to comprehensively discover the genetic basis of neuroblastoma.</p>
| phs001436 | dbGaP
Project description:Purpose: Neuroblastoma is characterized by substantial clinical heterogeneity. Despite intensive treatment, the survival rates of high-risk neuroblastoma patients are still disappointingly low. Somatic chromosomal copy number aberrations have been shown to be associated with patient outcome, particularly in low- and intermediate-risk neuroblastoma patients. To improve outcome prediction in high-risk neuroblastoma, we aimed to design a prognostic classification method based on copy number aberrations. Methods: In an international collaboration, normalized high-resolution DNA copy number data (arrayCGH and SNP arrays) from 556 high-risk neuroblastomas obtained at diagnosis were collected from nine collaborative groups and segmented using the same method. We applied logistic and Cox proportional hazard regression to identify genomic aberrations associated with poor outcome. Results: In this study, we identified two types of copy number aberrations that are associated with extremely poor outcome. (i) Distal 6q losses were detected in 5.9% of patients and were associated with a ten-year survival probability of only 3.4%. (ii) Amplifications of regions not encompassing the MYCN locus were detected in 18% of patients and were associated with a ten-year survival probability of only 5.8%. Conclusion: Using a unique large copy number dataset of high-risk neuroblastoma cases, we identified a small subset of high-risk neuroblastoma patients with extremely low survival probability that might be eligible for inclusion in clinical trials of new therapeutics. The amplicons may also nominate alternative treatments that target the amplified genes.
2018-03-13 | GSE103123 | GEO
Project description:Stromal contamination is one of the major confounding factors in the analysis of primary solid tumor samples by single nucleotide polymorphism (SNP) arrays. As we propose to employ genome-wide SNP microarray analysis as a diagnostic platform for neuroblastoma, the sensitivity, specificity, and accuracy of these studies must be optimized. In order to investigate the effects of stroma, we derived early passage cell lines from nine primary tumors and compared their genomic signature with that of the primary tumors by 100K SNP array analysis. The average concordance between tumor and cell line for raw LOH (loss of heterozygosity) calls was 96% (range 91%-99%) and for raw copy number alterations (CNA), 71% (range 43%-87%). In general, there were a larger number of LOH events identified in the cell lines compared to the matched tumor samples (mean increase 3.2% ± 1.9%). We have developed an algorithm that shows that the presence of stroma contributes to under-reporting of LOH and copy number loss (CNL). Notable findings in this sample set were uniparental disomy (UPD) of chromosome arms 11p, 1q, 14q, and 15q and a novel area of amplification on chromosome band 11p15. Our analysis demonstrates that LOH was identified significantly more often in derived cell lines compared to the original tumor samples. While these may in part be due to clonal selection during adaptation to tissue culture, our study indicates contamination by normal stromal elements may be a major contributing factor in underestimation of LOH and CNL events. Keywords: genome wide SNP analysis Nine human neuroblastoma tumor samples with paired blood samples and derivative cell lines
2009-01-31 | E-GEOD-14656 | biostudies-arrayexpress
Project description:Neuroblastoma is a tumour of the sympathetic nervous system, with a clinical phenotype resulting from complex patterns of genetic abnormalities, accounting for the most common extracranial neoplasia in childhood. Here we report 44 copy number variations, validated by qPCR, in paired tumour and blood samples of seven patients with neuroblastoma. Thirty four genes were included in altered regions while 11 altered regions did not apparently contain known genes. Five changes were present both in tumour and blood DNA samples in four patients, suggesting presence of germline and/or somatic changes maintained throughout tumorigenesis. Furthermore, some similar or identical changes were observed in different patients. The X chromosome showed the largest number of alterations. DNA from peripheral blood and tumour samples was isolated following using Qiagen DNA Blood Mini Kit. Microarray assays were performed in an Affymetrix platform with Cytogenetics Whole-Genome 2.7 M Array® (Affymetrix, Inc., Santa Clara, CA) for detecting copy number variation across coverage of the whole genome with the highest density of markers for superior resolution. Assays were performed following the procedure of Cytogenetics Copy Number Assay User Guide (Affymetrix®) and analysed with the Affymetrix® Chromosome Analysis Suite (ChAS) software. Gains and losses in tumour and blood samples from each patient were estimated with 95% confidence intervals.
2014-01-01 | E-GEOD-43454 | biostudies-arrayexpress