Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

High-resolution copy number analysis of medulloblastoma

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Charles Eberhart

PROVIDER: E-GEOD-14437 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

Northcott Paul A PA Nakahara Yukiko Y Wu Xiaochong X Feuk Lars L Ellison David W DW Croul Sid S Mack Stephen S Kongkham Paul N PN Peacock John J Dubuc Adrian A Ra Young-Shin YS Zilberberg Karen K McLeod Jessica J Scherer Stephen W SW Sunil Rao J J Eberhart Charles G CG Grajkowska Wiesia W Gillespie Yancey Y Lach Boleslaw B Grundy Richard R Pollack Ian F IF Hamilton Ronald L RL Van Meter Timothy T Carlotti Carlos G CG Boop Frederick F Bigner Darrell D Gilbertson Richard J RJ Rutka James T JT Taylor Michael D MD

Nature genetics 20090308 4

We used high-resolution SNP genotyping to identify regions of genomic gain and loss in the genomes of 212 medulloblastomas, malignant pediatric brain tumors. We found focal amplifications of 15 known oncogenes and focal deletions of 20 known tumor suppressor genes (TSG), most not previously implicated in medulloblastoma. Notably, we identified previously unknown amplifications and homozygous deletions, including recurrent, mutually exclusive, highly focal genetic events in genes targeting histon ...[more]

PMID: 19270706

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Project description:Medulloblastoma is a highly aggressive pediatric brain tumor, in which expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However, the contribution of OCT4 transcript variants to tumor aggressiveness is still poorly understood. In this study, we found that transcripts encoding OCT4A, but not OCT4B or OCT4B1, were significantly correlated with LIN28A expression, which encodes another well-known pluripotency factor. LIN28A was found to specifically bind OCT4A transcripts and interact with poly(A) binding protein and RNA helicase A in polysomal fractions of medulloblastoma cells, favoring increased OCT4A protein levels in these cells. Medulloblastoma cells stably overexpressing OCT4A displayed significantly enhanced clonogenic activity, tumorsphere generation and invasion capability, as well as increased tumorigenicity. In an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic effects of OCT4A were found to be expression-level dependent and accompanied by distinct subchromosomal aberrations and differential expression of newly discovered, still poorly characterized, non-coding RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. Total RNA of 2-3 clones of each cell line (Control and OCT4A overexpression) was extracted with the RNeasy Mini kit (Qiagen), following the manufacturerâs protocol. Gene expression profiling was carried out independently for each sample using Affymetrix GeneChipÂ® Human Gene 2.0 ST whole-transcript arrays (Affymetrix, Santa Clara, CA, USA). The quality control and normalization of data were processed by AffymetrixÂ® Expression Console Software (Affymetrix). Differentially expressed genes were identified with the One-Way ANOVA, with a p-value cutoff of 0.05, using Transcriptome Analysis Console v3.0 (Affymetrix).

Dataset Information

High-resolution copy number analysis of medulloblastoma

Publications

Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma.

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