Genome-Wide Analysis of Somatic Copy Number Alterations and Gene Expression in Metastatic Melanoma: RNA-Seq
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE22932 | GEO | 2011/04/07
SECONDARY ACCESSION(S): PRJNA133097
REPOSITORIES: GEO
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Project description:All cancers are diseases of the genome. A combination of somatic point mutations, focal amplifications and deletions, and chromosome level aberrations conspire to disrupt gene expression and the interplay between signaling pathways that control normal growth and tissue homeostasis. Here we investigate somatic copy number abberations in metastatic melanomas.
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Project description:We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genome of 212 medulloblastomas, a malignant pediatric brain tumor. Focal amplifications of fifteen known oncogenes and focal deletions of twenty known tumor suppressor genes (TSG) were revealed, most not previously implicated in medulloblastoma. Importantly, we identified novel amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determining stem cell fates, and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing, and blocking the state of histone lysine methylation, particularly H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma. Keywords: Affymetrix SNP array
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Project description:We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genome of 212 medulloblastomas, a malignant pediatric brain tumor. Focal amplifications of fifteen known oncogenes and focal deletions of twenty known tumor suppressor genes (TSG) were revealed, most not previously implicated in medulloblastoma. Importantly, we identified novel amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histone lysine methylation, particularly histone 3, lysine 9 (H3K9). Post-translational modification of histone proteins is critical for regulation of gene expression, can participate in determining stem cell fates, and has been implicated in carcinogenesis. Consistent with our genetic data, restoration of expression of genes controlling H3K9 methylation greatly diminishes proliferation of medulloblastoma in vitro. Copy number aberrations of genes with critical roles in writing, reading, removing, and blocking the state of histone lysine methylation, particularly H3K9, suggest that defective control of the histone code contributes to the pathogenesis of medulloblastoma. Keywords: Affymetrix SNP array Genomic DNA isolated from fresh frozen primary human medulloblastomas and medulloblastoma cell lines were subjected to SNP genotyping using either Affymetrix 100K or 500K GeneChip Mapping array sets for the purpose of obtaining genome-wide copy number and LOH profiles.
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Project description:Epilepsy is a heterogenous group of disorders defined by recurrent seizure activity due to abnormal synchronized activity of neurons. A growing number of epilepsy cases are believed to be caused by genetic factors and copy number variants (CNV) contribute to up to 5% of epilepsy cases. However, CNVs in epilepsy are usually large deletions or duplications involving multiple neurodevelopmental genes. Here we identify focal amplifications of regulatory regions of receptor tyrosine kinase genes as a genetic abnormality in epileptogenic brains. Whole genome DNA methylation profiling identified three main clusters of which one showed strong association with receptor tyrosine kinase genes. By copy number analysis, we identified focal copy number gains involving EGFR and PDGFRA in brain tissue of patients who underwent seizure focus resection for treatment-resistant epilepsy. The dysplastic neurons showed marked overexpression of pEGFR and pPDGFRA, while glial and endothelial cells were negative. Sequencing and DNA methylation analysis revealed that enhancer regions of EGFR and PDGFRA gene promoter were amplified, while coding regions did not show copy number abnormalities or somatic mutations. Our results identify somatic focal copy number gains of noncoding regulatory regions in the brain as a previously unrecognized genetic driver in epilepsy. Somatic copy number aberrations of regulatory regions represent a mechanism of abnormal activation of receptor tyrosine kinase genes in epilepsy. Upregulated receptor tyrosine kinases provide a potential avenue for therapy in seizure disorders.
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