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Codeletion of 1p and 19q Determines Distinct Gene Methylation and Expression Profiles in IDH-mutated Oligodendroglial Tumors

ABSTRACT: Genome wide DNA methylation profiling of oligodendroglial tumors (OTs) and five non tumoral brain tissue (NTBT) samples. The Illumina Infinium Human DNA methylation 450k Beadchip was used to obtain DNA methylation profiles across approximately 450,000 CpGs in tumoral samples. Samples included 46 OTs and 5 NTBT.

ORGANISM(S): Homo sapiens

PROVIDER: GSE61160 | GEO | 2014/09/06

SECONDARY ACCESSION(S): PRJNA260370

REPOSITORIES: GEO

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Project description:Purpose: The most clearly established genetic hallmark in oligodendroglial tumors (OTs) is the combined loss of 1p/19q, a molecular alteration characteristic of tumors responding to therapy. Markers of tumoral progression have not yet been studied. Experimental Design: Novel markers of tumoral progression in OTs were sought through gene expression profiling analysis. Results: Unsupervised hierarchical cluster analysis classified OTs into two main groups associated with tumoral grade, independent of histological subtype and 1p/19q status. Differential gene expression analysis between low- and high-grade OTs revealed that only cell cycle-related genes were significantly upregulated in high-grade OTs. Among the deregulated genes, NDRG2 downregulation was detected in high-grade OTs with combined loss of 1p/19q. Expression analysis revealed low transcript levels of NDRG2 relative to non-tumoral brain tissue in 45% (9/20) of high-grade OTs. Furthermore, the low transcript levels of NDRG2 were significantly associated with a worse clinical outcome in patients. Transcript levels of NDRG2 were associated with promoter hypermethylation, which was detected in 38.4% (10/26) of high-grade OTs. The treatment of glioma cell lines T98 and LN18 with demethylating agents increased the mRNA expression levels of NDRG2 relative to the control cell line. Additionally, cell proliferation was significantly reduced and cell cycle was arrested in G1 phase after treatment with demethylating agents. Conclusions: Taken together, our results suggest that NDRG2 is a candidate tumor suppressor gene in OTs whose inactivation could be involved in tumoral progression and worse patient survival. The microarray study involved 28 glioma samples including oligodendrogliomas and oligoastrocytomas WHO grade II and III. Six non-tumoral brain tissues were used as controls, two of which were purchased from Stratagene (La Jolla, CA) and Clontech (Mountain View, CA). RNAs from several cell lines (Universal Human RNA, Stratagene, La Jolla, CA) was used as a standard reference in all hybridizations

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Codeletion of 1p and 19q Determines Distinct Gene Methylation and Expression Profiles in IDH-mutated Oligodendroglial Tumors

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