BIOM-105. TRANSCRIPTOMIC INSIGHTS INTO LNCRNA-MEDIATED PATHWAYS ACROSS MEDULLOBLASTOMA SUBTYPES

Abstract Medulloblastoma, comprising ~20% of pediatric brain tumors, is classified into four molecular subgroups (WNT, SHH, Group 3, Group 4) with distinct prognostic features. Further heterogeneity has been revealed in Group 3/4 through methylation-based sub-classification. Long non-coding RNAs (lncRNAs) make a large part of the regulatory transcriptome and have been reported to take part in cellular function and disease progression. This study aims to identify subtype-specific lncRNAs in medulloblastoma and assess their potential as prognostic markers and therapeutic targets. We analyzed RNA-sequencing data from 63 medulloblastoma samples from the Luo, Zaili et al. dataset. LncRNAs were filtered based on GENCODE annotations and differential expression analysis was conducted. Interactions of the differentially expressed lncRNAs were identified via databases and literature review. WGCNA revealed lncRNA-related genes, which were applied to 320 Group 3/4 samples for dimensionality reduction and subtype clustering. Feature selection was performed on the genes and was validated by UMAP, followed by pathway enrichment analysis. Our analysis revealed lncRNAs involved in critical oncogenic pathways. Specifically, the WNT-unique lncRNA HAND2-AS1 was negatively correlated, while Group 3-unique lncRNAs LINC01139/LINK-A was positively correlated with key genes like HIF1α, TGFβ1, ROCK1, and BCL2, which are linked to angiogenesis, metastasis, and cell proliferation. WGCNA identified a HAND2AS1-related module consisting of 800 genes. PCA and UMAP clustering on the GSE85217 dataset using genes in the HAND2AS1-related module showed clear separation of Group 3/4 subtypes. Feature selection narrowed the gene set to 117 without losing cluster integrity. Top enriched pathways included WNT signaling, N-Glycan biosynthesis, and protein processing in the endoplasmic reticulum. This study highlights subtype-specific lncRNAs, particularly HAND2-AS1, as potential biomarkers and therapeutic targets in medulloblastoma. The HAND2-AS1-associated gene module enabled distinct clustering of Group 3/4 subtypes, even after feature selection, underscoring its robustness. Enrichment in WNT signaling and protein processing pathways further supports its role in MB pathogenesis and subtype stratification.