Copy number alterations in pleural mesothelioma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE21057 | GEO | 2010/07/01
SECONDARY ACCESSION(S): PRJNA129693
REPOSITORIES: GEO
Similar Datasets
Project description:Integrated profiling of somatic molecular alterations present in tumors is necessary to further our understanding of the tumorigenic process. We investigated the potential relationships between gene copy number alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n=23). Gene copy number (CN) alterations profiled with 500K SNP arrays and DNA methylation measured at over 750 cancer-related genes with methylation bead-arrays were examined concomitantly. Considering each probed locus, there were no instances of significantly correlated CN alteration and methylation (no loci with Q < 0.05) and averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations (Q < 0.04). In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes (P < 0.02), and there was evidence that this association was partially attributable to prevalent allele loss observed at the maintenance DNA methyltransferase DNMT1. Taken together, this work indicates a strong association between global genetic and global epigenetic dysregulation in mesothelioma rather than a discrete, local coordination of gene inactivation, and further highlights the utility and necessity of integrative genomics approaches in cancer biology.
2010-07-01 | GSE20989 | GEO
Project description:Integrated profiling of somatic molecular alterations present in tumors is necessary to further our understanding of the tumorigenic process. We investigated the potential relationships between gene copy number alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n=23). Gene copy number (CN) alterations profiled with 500K SNP arrays and DNA methylation measured at over 750 cancer-related genes with methylation bead-arrays were examined concomitantly. Considering each probed locus, there were no instances of significantly correlated CN alteration and methylation (no loci with Q < 0.05) and averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations (Q < 0.04). In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes (P < 0.02), and there was evidence that this association was partially attributable to prevalent allele loss observed at the maintenance DNA methyltransferase DNMT1. Taken together, this work indicates a strong association between global genetic and global epigenetic dysregulation in mesothelioma rather than a discrete, local coordination of gene inactivation, and further highlights the utility and necessity of integrative genomics approaches in cancer biology. From the total study population, 23 tumors from the incident case series were chosen for copy number alteration profiling by hybridizing 5ml containing ⥠50ng/ml of tumor or matched peripheral blood DNA to each of the two GeneChips® that comprise the Human Mapping 500K single-nucleotide polymorphism array set (Affymetrix, Santa Clara, CA), following manufacturer protocols and standard operating procedures at the Harvard Partners Microarray Core servicing facility. Probe intensities at each locus were determined in the GCOS software and genotypes calls were generated using the Genotyping Analysis Software (Affymetrix). Probe signals were normalized to their matched referent peripheral blood sample data using the Copy Number Analysis Tool v4.0.1 software (CNAT) (Affymetrix) with median scaling and default tuning parameters, and copy number states were inferred by Hidden Markov Model analysis. The supplementary file 'GSE21057_tumor_copy_number.txt' contains the (blood-normalized) copy number calls for each tumor sample.
2010-07-31 | E-GEOD-21057 | biostudies-arrayexpress
Project description:Integrated profiling of somatic molecular alterations present in tumors is necessary to further our understanding of the tumorigenic process. We investigated the potential relationships between gene copy number alterations and DNA methylation profiles in a case series of pleural mesotheliomas (n=23). Gene copy number (CN) alterations profiled with 500K SNP arrays and DNA methylation measured at over 750 cancer-related genes with methylation bead-arrays were examined concomitantly. Considering each probed locus, there were no instances of significantly correlated CN alteration and methylation (no loci with Q < 0.05) and averaging loci over their associated genes revealed only two genes with significantly correlated CN and methylation alterations (Q < 0.04). In contrast to the lack of discrete correlations, the overall extent of tumor CN alteration was significantly associated with DNA methylation profile when comparing CN alteration extent among methylation profile classes (P < 0.02), and there was evidence that this association was partially attributable to prevalent allele loss observed at the maintenance DNA methyltransferase DNMT1. Taken together, this work indicates a strong association between global genetic and global epigenetic dysregulation in mesothelioma rather than a discrete, local coordination of gene inactivation, and further highlights the utility and necessity of integrative genomics approaches in cancer biology. Mesotheliomas were obtained following surgical resection at Brigham and Women’s Hospital through the International Mesothelioma Program from a pilot study conducted in 2002 and an incident case series beginning in 2005 as previously described (PMIDs: 19118007 and 19638575). All patients provided informed consent under the approval of the appropriate Institutional Review Boards. Clinical information, including histologic diagnosis was obtained from pathology reports. The study pathologist confirmed the histologic diagnoses and further assessed the percent tumor from resected specimens (mean >60%). DNA extraction and methylation analysis: DNA from fresh frozen tissue and matched whole blood was isolated with QIAamp DNA mini kit (Qiagen, Valencia, CA) following the manufacturer’s protocol. Tumor DNA was modified with sodium bisulfite using the EZ DNA Methylation Kit (Zymo Research, Orange, CA). Illumina GoldenGate® methylation bead arrays interrogated 1505 CpG loci associated with 803 cancer-related genes processed at the UCSF Institute for Human Genetics, Genomics Core Facility using methods described in (28). The GoldenGate methylation data used in the analysis has been previously described (PMIDs: 19118007 and 19638575).
2010-07-01 | E-GEOD-20989 | biostudies-arrayexpress
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However, at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood references were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1. This study was designed to investigate the relationship between copy number and DNA methylation alterations in head and neck squamous cell carcinoma. Data in this submission relates to the copy number portion only. Each patient tumor has been de-identified and assigned a number (1-19) and the blood samples with the same number correspond to the respectively-numbered tumor. The supplementary file 'GSE20939_tumor_copy_number.txt' contains the (blood normalized) copy number calls for each tumor sample.
2010-11-11 | E-GEOD-20939 | biostudies-arrayexpress
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood referents were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1.
2010-03-11 | GSE20742 | GEO
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However, at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood references were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1.
2010-03-18 | GSE20939 | GEO
Project description:Solid tumors, including head and neck squamous cell carcinomas (HNSCC), arise as a result of genetic and epigenetic alterations in a sustained stress environment. Since it has been hypothesized that epigenetic alterations may act by providing the second carcinogenic hit in gene silencing, we sought to identify genome-wide DNA copy number alterations and CpG dinucleotide methylation events and examine the global/local relationships between these types of alterations in HNSCC. Importantly, we found that the global pattern of copy number alterations in these tumors was significantly associated with tumor methylation profiles. However at the local level, gene promoter regions did not exhibit a correlation between copy number and methylation , and the spectrum of genes affected by each type of alteration was unique. A case-series of 19 tumors and matched blood referents were hybrizided to Affymetrix Human Mapping 500k arrays and copy number was determined via HMM with Copy Number Analysis Tool v4.0.1. This study was designed to investigate the relationship between copy number and DNA methylation alterations in head and neck squamous cell carcinoma. Data in this submission relates to the methylation portion only. Each patient tumor has been de-identified and assigned a number (1-19). We included 11 normal head and neck samples, procured through the National Research Disease Interchange, that were used for reference when comparing tumor to normal. One ug of tissue DNA extracted using the Qiagen Blood and Tissue Kit was bisulfite-modified using a Zymo Research EZ DNA Methylation Kit. Samples were processed and arrayed on the Illumina GoldenGate Methylation Cancer Panel 1 at the University of California-San Francisco Institute for Genetics, Genomic Core Facility.
2010-06-23 | E-GEOD-20742 | biostudies-arrayexpress
Project description:Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations and even more in women. Since epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) fusions are major alterations found in NSLA, studies have focused on NSLA with EGFR and ALK alteration (EA), but not for NSLA without EGFR and ALK alteration (NENA). To reveal the proteogenomic landscape of NENA, we selected 101 NSLA tissues without EGFR and ALK by targeted sequencing of 1597 FFPE samples, and performed multiomics analyses including whole genome, transcriptome, methylation EPIC array, total proteome, and phosphoproteome. Genome analysis revealed that TP53 (25%), KRAS (22%), ROS1 fusion (13%), SETD2 (11%), and ERRB2 (9%) were the most frequently mutated genes in NENA. Proteogenomic impact analysis found that STK11 and ERBB2 somatic mutations had more profound effects on cancer-associated genes in NENA. From DNA copy number alteration analysis, we identified 22 prognostic proteins whose expression was controlled through transcriptome from copy number alterations Intriguingly, from gene set enrichment analysis, estrogen signaling emerged as the key pathway activated in NENA compared with EA. Evidence from multiomics analysis including copy number gains in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14, also supported the increased estrogen signaling. Finally, the saracatinib, an Src inhibitor, was suggested as a potential drug for targeting activated estrogen signaling in NENA. Taken together, the proteogenomic landscape for NENA from this study will enhance our understanding of the etiology of NSLA.
2024-03-12 | PXD033360 | Pride
Project description:The integration of genomic and epigenomic data is becoming increasingly popular as we try to gain better understanding of the complex mechanisms driving the development and progression of cancer. However, this results in increased cost and sample depletion, the latter being particularly important when considering intra-tumour heterogeneity. We therefore sought to investigate the possible utility of high-density DNA methylation arrays to assess both aberrant methylation as well as changes in gene copy number. Comparing CN (Copy Number) data derived from the Infinium Human Methylation 450K arrays with that generated on SNP arrays, we demonstrate the utility of the Infinium arrays to detect single copy alterations as well as homozygous deletions and high level amplification with the reliability of current gold standard platforms. Furthermore, we show that the gene centric design of the Infinium methylation arrays allows identification of small single gene alterations, which would not be detected using standard SNP array analysis. These results show that Infinium 450K methylation arrays provide a robust and economic platform for detecting copy number and methylation changes in a single experiment. The ability to integrate such data from the same sample is critical for cancer research and will improve our understanding of how complex genomic and epigenomic interactions are driving the development and progression of a malignant phenotype. Extracted DNA from each sample was hybridised to Illumina CytoSNP12 v2.1 BeadChips.
2016-05-31 | E-GEOD-48941 | biostudies-arrayexpress
Project description:Alterations in DNA copy number contribute to the development and progression of cancers and are common in epithelial tumors. We have used array Comparative Genomic Hybridization (aCGH) to visualize DNA copy number alterations across the genomes of lung tumors in the KrasLA2 model of lung cancer. Copy number gain involving the Kras locus, as focal amplification or whole chromosome gain, is the most common alteration in these tumors, and with a prevalence that increased significantly with increasing tumor size. Furthermore, Kras amplification was the only major genomic event among the smallest lung tumors, suggesting that this alteration occurs early during the development of mutant Kras driven lung cancers. Recurring gains and deletions of other chromosomes occur progressively more frequently among larger tumors. These results are in contrast to a previous aCGH analysis of lung tumors from KrasLA2 mice on a mixed genetic background, in which relatively few DNA copy alterations were observed regardless of tumor size. Our model features the KrasLA2 allele on the inbred FVB/N mouse strain, and in this genetic background there is a highly statistically significant increase in level of genomic instability with increasing tumor size. These data suggest that recurring DNA copy alterations are important for tumor progression in the KrasLA2 model of lung cancer, and that the requirement for these alterations may be dependent on the genetic background of the mouse strain.
2011-11-22 | GSE29230 | GEO