Copy number analysis of high-grade osteosarcoma
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Marieke Kuijjer
PROVIDER: E-GEOD-33153 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:High-grade osteosarcoma is a tumor with a complex genomic profile, occurring primarily in adolescents with a second peak at middle age. The extensive genomic alterations obscure the identification of genes driving tumorigenesis during osteosarcoma development. In order to identify such driver genes, we integrated DNA copy number profiles (Affymetrix SNP 6.0) of 32 diagnostic biopsies with 84 expression profiles (Illumina Human-6 v2.0) of high-grade osteosarcoma as compared with its putative progenitor cells, i.e. mesenchymal stem cells (n=12) or osteoblasts (n=3). In addition, we performed paired analyses between copy number and expression profiles of a subset of 29 patients for which both DNA and mRNA profiles were available. Integrative analyses were performed in Nexus Copy Number software and statistical language R. Paired analyses were performed on all probes detecting significantly differentially expressed genes in corresponding LIMMA analyses. For both non-paired and paired analyses, copy number aberration frequency was set to >35%. Non-paired and paired integrative analyses resulted in 45 and 101 genes, respectively, which were present in both analyses using different control sets. Paired analyses detected >90% of all genes found with the corresponding non-paired analyses. Remarkably, approximately twice as many genes as found in the corresponding non-paired analyses were detected. Affected genes were intersected with differentially expressed genes in osteosarcoma cell lines, resulting in 31 new osteosarcoma driver genes. Cell division related genes, such as MCM4 and LATS2, were overrepresented and genomic-instability was predictive for metastasis-free survival, suggesting that deregulation of the cell cycle is a driver of osteosarcomagenesis. This SuperSeries is composed of the following subset Series: GSE28974: Genome-wide gene expression profiling of mesenchymal stem cells GSE33153: Copy number analysis of high-grade osteosarcoma GSE33382: Genome-wide gene expression analysis of high-grade osteosarcoma For data processing, we refer to the individual series. We performed both non-paired and paired integrative analyses on SNP and gene expression data. Non-paired integrative analysis was performed by importing lists of differentially expressed genes into the Copy Number module of Nexus software version 5 (BioDiscovery, CA). Based on the length of the gene list, Nexus software performs a Fisher's exact test in order to determine whether the number of differentially expressed genes in a specific region with a significant copy number alteration is larger than expected by chance. Genes present in such regions of copy number alteration with FDR-adjusted P-values (Q-bounds in Nexus software) < 0.05 were returned from this integrative analysis. Nexus software only reports genes which are both gained and overexpressed, or both deleted and downregulated. For the paired integrative analysis, copy number data of all autosomal overlapping genes between the copy number and gene expression arrays were exported from Nexus software, and converted into a binary file containing all genes with a gain (1) and no gain (0), and a similar binary file for losses. As in the non-paired integrative analysis, we did not apply any restrictions on the size of copy number alterations. Gene expression data of each probe for each sample were normalized against average gene expression of the corresponding probes over all control samples (either expression data from 12 MSCs, or from 3 osteoblasts). This was performed by subtracting the average expression of the control samples from the expression levels of the sample of interest, since these are log-transformed expression values. For both analyses, only genes that were significantly differentially expressed between the 84 osteosarcoma samples and the specific control set were analyzed, in order to make sure that no genes returned from the integrative analysis were not significantly differentially expressed. Subse quently, genes that overlapped between the copy number binary files and that matched the fold change of expression (upregulation for genes with gains, and downregulation for genes with losses) were returned.
2012-03-27 | E-GEOD-33383 | biostudies-arrayexpress
Project description:Osteosarcomas are the most common primary malignant tumours of bone, and almost all conventional osteosarcomas are high-grade tumours showing complex genomic aberrations. We have integrated genome-wide genetic and epigenetic profiles from the EuroBoNeT panel of 19 human osteosarcoma cell lines based on microarray technologies. The cell lines showed complex patterns of DNA copy number changes, where copy number gains were significantly associated with gene-rich regions of the genome and losses with gene-poor areas. Integration of the datasets showed that the mRNA levels were regulated by either alterations in DNA copy number or DNA methylation. Using a recurrence threshold of 6/19 (> 30 %) cell lines, 348 genes were identified as having alterations of two data types (gain or hypo-methylation/over-expression, loss or hyper-methylation/under-expression). These genes are involved in embryonic skeletal system development and morphogenesis, as well as remodelling of extracellular matrix. Several genes were hyper-methylated and under-expressed compared to normal osteoblasts, and expression could be reactivated by demethylation using 5-Aza-2M-bM-^@M-^Y-deoxycytidine treatment for all four genes tested. Globally, there was as expected a significant positive association between gain and over-expression, loss and under-expression as well as hyper-methylation and under-expression, but gain was also associated with hyper-methylation and under-expression, suggesting that hyper-methylation may oppose the effects of increased copy number for some genes. Integrative analysis of genome-wide genetic and epigenetic alterations identified mechanistic dependencies and relationships between DNA copy number and DNA methylation in terms of regulating mRNA expression levels in osteosarcomas, contributing to better understanding of osteosarcoma biology. Comparison of DNA copy number changes in 19 osteosarcoma cell lines
2012-12-06 | E-GEOD-36003 | biostudies-arrayexpress
Project description:Malignant mesothelioma (MM) is an asbestos-related malignancy. Discrimination between MM and reactive mesothelial hyperplasia (RM) is often difficult. MM cells have a broad histological spectrum, and consist mainly of epithelioid, sarcomatoid, and biphasic cell types. The prognosis of MM is generally poor, but better prognosis has been reported with the epithelioid type of MM than the non-epithelioid type. We applied a genome-wide analysis to the identification of new markers that may aid in differentiating the epithelioid type of MM from other histological types and from RM cells. Array-based comparative genomic hybridization analysis was performed on malignant mesothelioma (MM) primary cell cultures, reactive mesothelial hyperplasia (RM) primary cell cultures; early passage of in vitro primary cell cultures to minimize acquisition of additional genomic changes. If available, matched peripheral blood was applied to analysis.
2014-11-22 | E-GEOD-52788 | biostudies-arrayexpress
Project description:Integration of genomic copy number analysis (Affymetrix SNP6.0 arrays) and oncogenic RAS/RAF mutation status with clinical features and tumour progression. This study found that loss of the 9p and the CDKN2A locus with the most significantly enriched copy number aberration distinguishing serous border tumors from low grade serous carcinomas, suggesting this is a key step to tumor progression. Epithelial tissue from 57 serous borderline tumors (SBTs), 19 low grade serous carcinomas (LGSC)(data for 4 of the carcinomas have previously been submitted to GEO - Series GSE19539) and 355 high grade serous carinomas (HGSC)(TCGA, 2011; GSE19539; and 8 new) were analysed for copy number aberrations using Affymetrix SNP6.0 arrays and normalised SNP6.0 data. Stromal tissue from 38 SBT and 1 HGSC were analysed for copy number aberrations using Affymetrix SNP6.0 arrays. Matching lymphocyte DNA was availabe for 54 SBT, 3 LGSC and 1 HGSC. Sanger sequencing of KRAS, BRAF, NRAS, HRAS, ERBB2 and TP53 mutational hotspots was performed on the epithelial and stromal DNA. This information was then correlated with clinical features of the tumors.
2015-03-01 | E-GEOD-58579 | biostudies-arrayexpress
Project description:This study aimed to generate a new panel of comprehensively, genomically characterized high-grade serous ovarian carcinoma (HGSOC) cell line and xenograft models. Multidimensional genomic data were generated and compared between cell lines/xenografts and the tumours they were derived from, indicating the cell lines/xenografts are highly similar to their patient-matched tumours. Cell line/xenograft data were also compared to TCGA ovarian tumours to show the cell lines are good models of clinical HGSOC. Affymetrix SNP 6 arrays were performed according to the manufacturer's instructions on genomic DNA extracted from i) tumour cells purified from ovarian tumour ascites, ii) established cell lines, iii) patient derived xenografts, and iv) lymphoblast lines. Evaluation of the similarity in copy number/methylation/gene expression/mutational profiles of cell lines/tumours/xenografts was performed.
2016-08-11 | E-GEOD-71522 | biostudies-arrayexpress
Project description:Using xenograft-based experimental evolution, we characterize the full life history from initiation to metastasis of a tumor at the genomic and transcriptomic levels. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cell lines or xenograft tumor samples.
2014-11-27 | E-GEOD-63630 | biostudies-arrayexpress
Project description:We report a deletion on 11q13.3-q13.4 in one patients with severe mental retardation. We analyzed a patient with mental retardation and the related parents with a whole genome SNP Array.
2010-05-28 | E-GEOD-20533 | biostudies-arrayexpress
Project description:DNA copy number alterations and mutations were characterised by bulk SNP anlaysis and exome sequencing (not sown here) in three acute lymphoblastic leukaemia samples and one establish cell line REH. Further single cell experiments of these cases investigated the mutation and copy number targets previously defined exploring the sub-clonal populations and phylogenic trees within each leukaemia. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples. Copy number analysis of Affymetrix SNP6 arrays or Cytogenetics whole genome 2.7M arrays was performed for three leukaemic samples and one established cell line REH. Remission samples were only available for two of the leukaemia samples (Case A and Case B) and therefore 20 HapMap Caucasien samples were used as controls for the SNP6 array expeeriments.
2013-07-26 | E-GEOD-49215 | biostudies-arrayexpress
Project description:Osteosarcoma in dogs is a spontaneously occurring disease with a global tumor gene expression signature indistinguishable from human pediatric tumors and clinical progression is remarkably similar. Unlike human OS, canine OS is a highly heritable disease with some large and giant dog breeds at >10x increased risk. We did a genome wide association study of osteosarcoma using the Illumina CanineHD genotyping array in three breeds: greyhound (mortality from OS = 26%), rottweiler (17%) and Irish wolfhound (IWH, 21%) and identified 33 inherited risk loci explaining 55 to 85% of phenotype variance in each breed. Data created for a genome-wide association studio of heritable osteosarcoma risk factors in dogs, including 267 racing greyhounds (153 affected (A) + 114 unaffected (U)), 135 rottweilers (80 A + 55 U), 141 IWH (76 A + 65 U) and 19 AKC greyhounds using the Illumina CanineHD array (~170,000 SNPs genomewide)
2013-11-12 | E-GEOD-51734 | biostudies-arrayexpress
Project description:Osteosarcoma in dogs is a spontaneously occurring disease with a global tumor gene expression signature indistinguishable from human pediatric tumors and clinical progression is remarkably similar. Unlike human OS, canine OS is a highly heritable disease with some large and giant dog breeds at >10x increased risk. We did a genome wide association study of osteosarcoma using the Illumina CanineHD genotyping array in three breeds: greyhound (mortality from OS = 26%), rottweiler (17%) and Irish wolfhound (IWH, 21%) and identified 33 inherited risk loci explaining 55 to 85% of phenotype variance in each breed. Data created for a genome-wide association studio of heritable osteosarcoma risk factors in dogs, including 267 racing greyhounds (153 affected (A) + 114 unaffected (U)), 135 rottweilers (80 A + 55 U), 141 IWH (76 A + 65 U) and 19 AKC greyhounds using the Illumina CanineHD array (~170,000 SNPs genomewide)
2013-11-12 | E-GEOD-51973 | biostudies-arrayexpress