P10.09.B Retroelement expression in glioma tumors exhibits subtype specific patterns

Abstract

Background There are ~3 million transposable elements in the human genome constituting about 42% of all basepairs. Retroelements (REs) are ~90% of the transposable elements present in the human genome. Active REs are considered highly mutagenic and have been implicated in multiple steps of cancer development and progression, as well as in neurologic diseases. RE activity has functional effects on the genome, including the maintenance of centromere and telomere integrity, and deleterious gene expression. Previous studies have shown that certain families of RE (HERVK, L1, Alu) are expressed in gliomas, however, their specific role as arbitrators of oncogenesis or promoters of the innate anti-tumor immune response remains uncertain. Moreover, it has been shown that a soluble form of PD-L1 (sPD-L1) that blocks its inhibitory activity is produced by exaptation of an intronic endogenous retroelement (LINE-2A) in the gene encoding PD-L1, highlighting the importance of REs as potential therapeutic targets. In this analysis we aim to identify the unique patterns of RE expression across major subtypes of glioma. Material and Methods We conducted a differential expression analysis of 49 RE families using RNA-seq data measured in glioma tumors from The Cancer Genome Atlas (TCGA). RE counts were produced using the software REDiscoverTE. Pairwise comparisons between glioma subtypes (defined by WHO2021) were done using in 625 tumor samples adjusting for age, sex and race. Results 10 of the 49 considered RE families exhibited significantly different (false discovery rate, FDR, <0.05) expression in at least one glioma subtype. Alu(Fold change, FC=1.5), RNA(FC=11.3), PiggyBac(FC=1.6), rRNA(FC=5.23) and Dong-R4(FC=1.8) were overexpressed in IDH-wildtype glioblastoma while Gypsy(FC=0.4) and CRP1(FC=0.26) were decreased in expression. scRNA (FC=2.7) were overexpressed in IDH-mutant oligodendroglioma compared to glioblastoma while Dong-R4 (FC = 0.53) showed decreased expression. LTR (FC=2.02) and tRNA-Deu (FC=1.46), showed increased expression in IDH-wildtype diffuse astrocytomas compared to IDH-mutant, 1p/19q-codeleted oligodendrogliomas while Gypsy (FC =0.41) showed decreased expression. Conclusion We have shown that expression of certain RE families within gliomas have subtype-specific patterns. While it is well established that RE expression is dysregulated in cancer, our analysis is the first at exploring a wide range of retroelements in the context of glioma by subtype. Given the important role of REs in transcriptional control, genomic instability, chromosomal rearrangements, and oncogenic activation, the identification of individual families and specific REs in glioma holds an intrinsic value to potential biomarkers and immunotherapy targets.