Enhancer RNA transcriptome-wide association study reveals an atlas of pan-cancer susceptibility eRNAs

Many cancer risk variants are located within enhancer regions and lack sufficient molecular interpretation. Here, we constructed the first comprehensive atlas of enhancer RNA (eRNA)- mediated genetic effects from 28,033 RNA sequencing samples across 11,606 individuals, identifying 11,757 eRNA quantitative trait loci (eRNA-QTLs) significantly associated with eRNA expression. Mechanistically, eRNA-QTLs frequently altered binding motifs of transcription factors. In addition, 28.48% of cancer risk variants were strongly colocalized with eRNA-QTLs. We further performed an eRNA-based transcriptome-wide association study and identified 626 cancer susceptibility eRNAs across 23 cancer types. 54.9% of the eRNA target genes were overlooked by traditional gene expression studies, and most are essential for cancer cell proliferation. To substantiate our findings, we confirmed the enhancer functionality of two newly identified susceptibility eRNAs, CCND1e and SNAPC1e, through CRISPR-based inhibition, resulting in a marked decrease in the expression of their respective target genes, consequently suppressing the proliferation of prostate cancer cells. Our study underscores the essential role of eRNA in unveiling new cancer susceptibility genes and establishes a strong framework for enhancing our understanding of human cancer etiology.