Systematic decoding the functional role of human endogenous retrovirus-derived RNAs in medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, but its pathogenesis remains poorly understood. Although human endogenous retrovirus-derived RNAs (hervRNAs) are implicated in tumorigenesis across various cancers, their functional role in the pathogenesis of MB has not been discovered.

We collected total RNA samples from 63 pediatric MB patients for RNA sequencing and identified the expression of hervRNAs in a locus-specific manner. The functional role of hervRNAs was analyzed through independent expression analysis, gene set enrichment analysis, weighted correlation network analysis, and further validated by siRNA-knockdown experiment in D283 cells.

We systematically identified 39,613 MB-expressed hervRNAs and found that their expression profile could distinguish the four consensus molecular subgroups. Specifically, 145 subgroup-specific hervRNAs were identified to be significantly associated with tumor development. Functional annotation revealed that these hervRNAs were enriched in known MB subgroup-related pathways but also implied novel pathways related to regulated necrosis, negative regulation of class C GPCR, extracellular matrix remodeling, as well as DNA methylation. Notably, the expression of Group3-specific hervRNAs showed a significant negative correlation with promoter DNA methylation levels. Experimental validation confirmed that Group3-specific hervRNA_G38830 and hervRNA_G66017 inhibit cell proliferation and promote apoptosis. Finally, a semi-quantitative model based on 70 hervRNA clusters achieved molecular classification with accuracy above 94.8%.

Our work provided insights into MB tumorigenesis in the layer of hervRNA, uncovering potential targets for therapeutic intervention and novel biomarkers for molecular classification.