TMEM161B-AS1: a pivotal long non-coding RNA in the pathogenesis of glioblastoma revealed by Mendelian randomization...

The significance of long non-coding RNAs (lncRNAs) in glioblastoma multiforme (GBM) has been acknowledged, but their specific role in the pathogenesis of GBM has not been thoroughly investigatedr. This study aimed to investigate the involvement of lncRNAs in the pathogenesis of GBM.

We collected GBM tissues from four patients and corresponding para-carcinoma controls samples, and used HiSeq sequencing to generate lncRNA expression profiles in GBM. To identify lncRNAs associated with GBM, we employed Mendelian randomization (MR), leveraging the comprehensive extensive expression data obtained from HiSeq sequencing to infer causal relationships. Expression quantitative trait loci (eQTLs) for brain tissues were accessed from the Genotype-Tissue Expression (GTEx) Portal. Subsequently, we conducted an integrative analysis combining brain cancer genome-wide association study (GWAS) summary data (finn-b-C3_GBM) with eQTL data using MR. Differentially expressed lncRNAs were intersected with MR results to identify lncRNA candidates. Subsequently, the ENCORI database was used to identify genes regulated by the candidate lncRNAs, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed.

A protein-protein interaction (PPI) network was constructed to identify hub genes associated with GBM, and these findings were validated using the Gene Expression Profiling Interactive Analysis 2 (GEPIA2) tool. A total of 106 lncRNAs exhibited significant alterations in expression levels (|log₂(fold change)| > 1 and P < 0.05) in GBM tissues. Through Mendelian randomization (MR) analysis, TMEM161B-AS1 emerged as a promising candidate lncRNA. Genes regulated by TMEM161B-AS1 were significantly enriched in biological processes such as DNA replication and repair, cellular response to DNA damage stimuli, and pathways including the peroxisome proliferator-activated receptor signaling pathway, nucleotide excision repair, and the Fanconi anemia pathway. The differential expression of hub genes CUL4A, RPA1, and BRIP1 was validated using the GEPIA2 database.

These findings suggest pathways for the development of more precise and sensitive biomarkers for the diagnosis and management of GBM, which may ultimately enhance patient outcomes.