Distal gene regulation mediated by non-coding RNAs contributes to germline risk for breast and prostate cancer

Genome-wide association studies (GWAS) have identified numerous genetic loci associated with breast and prostate cancer risk, suggesting that germline genetic dysregulation influences tumorigenesis. However, the biological function underlying many genetic associations is not well-understood. Previous efforts to annotate loci focused on protein-coding genes (pcGenes) largely ignore non-coding RNAs (ncRNAs) which account for most transcriptional output in human cells and can regulate transcription of both pcGenes and other ncRNAs. Though the biological roles of most ncRNAs are not well-defined, many ncRNAs are involved in cancer development. Here, we explore one regulatory hypothesis: ncRNAs as trans-acting mediators of gene expression regulation in non-cancerous and tumor breast and prostate tissue. Using germline genetics as a causal anchor, we categorize distal (>1 Megabase) expression quantitative trait loci (eQTLs) of pcGenes significantly mediated by local-eQTLs of ncRNAs (within 1 Megabase). We find over 300 mediating ncRNAs and show the linked pcGenes are enriched for immunoregulatory and cellular organization pathways. By integrating eQTL and cancer GWAS results through colocalization and genetically-regulated expression analyses, we detect overlapping signals in nine known breast cancer loci and one known prostate cancer locus, and multiple novel genetic associations. Our results suggest a strong transcriptional impact of ncRNAs in breast and prostate tissue with implications for cancer etiology. More broadly, our framework can be systematically applied to functional genomic features to characterize genetic variants distally regulating transcription through trans-mechanisms. SIGNIFICANCEThis study identifies non-coding RNAs that potentially regulate gene expression in trans-pathways and overlap with genetic signals for breast and prostate cancer susceptibility, with implications for interpretation of cancer genome-wide association studies.