Exploring genetic variants of lncRNA associated with splicing regulation and their impact on ovarian cancer development

Ovarian cancer (OC) is a highly lethal gynecologic malignancy that lacks reliable early biomarkers. Numerous long non-coding RNAs (lncRNAs) have been found to play critical regulatory roles in OC, yet the underlying mechanisms of most of them remain unclear. Recently, lncRNAs have emerged as key regulators of gene splicing, while splicing dysregulation is widespread in cancer and plays critical roles. In addition, genetic variants of splicing regulators have been shown to contribute to disease etiology. Thus, we comprehensively analyzed 202 OC samples and characterized 21,129 lncRNA splicing quantitative trait loci (sQTLs) involving both event-level and transcript-level. LncRNA sQTLs differ significantly from lncRNA eQTLs, and genes regulated by lncRNA sQTLs are involved in cancer hallmark pathways and associated with immune cell infiltration and drug sensitivity. In addition, these lncRNA sQTLs are significantly enriched in histone markers, transcription factor (TF) binding sites, and RNA-binding protein (RBP) binding sites, including several critical splicing factors (SF) in OC. Based on SF binding and partial correlation analysis, a potential lncRNA-SF-mRNA regulatory network was constructed. Finally, by integrating GWAS data, we elucidated that a specific lncRNA sQTL (rs1549334) generates different isoforms by regulating the splicing of the HOXD3 gene and thus impacting OC risk. Our study provides new insights into the mechanisms of splicing regulation in OC involving lncRNA sQTL and reveals potential biomarkers for early detection and clinical treatment of OC.