Promoter methylation-associated brain-enriched long noncoding RNAs in glioblastoma: a multi-cohort public epigenomic re-analysis.

BACKGROUND

Glioblastoma (GBM) is epigenetically heterogeneous, and previous long noncoding RNA (lncRNA) methylation studies have often begun from tumor-wide screens. We asked whether brain-enriched lncRNAs show promoter methylation-associated suppression in GBM.

RESEARCH DESIGN AND

METHODS

Brain-enriched lncRNAs were defined using GENCODE v49 and GTEx/UCSC Xena. Primary discovery used TCGA-GBM primary tumors with matched expression and promoter methylation; 52 patients had both data types. Spearman correlations identified methylation-associated candidates (ρ ≤-0.30; false discovery rate [FDR] < 0.05). External layers used GSE36278 methylation, CGGA expression/survival, and GSE131928 Smart-seq2 state scores.

RESULTS

Of 13,213 lncRNAs, 437 were brain-enriched and 76 entered matched TCGA analysis; seven met core criteria. PTPRD-AS1 and NFIB-AS1 showed the strongest inverse coupling (ρ = -0.665 and -0.639; FDR = 0.000016 and 0.000028). GSE36278 supported hypermethylation direction for all seven candidates, with six FDR-significant. MEG8 and FAM201A were downregulated in CGGA versus GTEx brain, and FAM201A associated with pseudobulk stemness and mesenchymal scores.

CONCLUSIONS

This public-data re-analysis prioritizes brain-enriched lncRNAs associated with promoter hypermethylation and lower expression in GBM, but does not establish direct methylation-mediated silencing.