Deciphering genetic susceptibility to clear cell renal cell carcinoma.

Genome-wide association studies (GWAS) have identified over 60 autosomal risk loci associated with clear cell renal cell carcinoma (ccRCC), yet the functional mechanisms underlying these associations remain largely unclear. To establish connections between risk variants and their target genes, we applied the activity-by-contact (ABC) model, which integrates epigenomic data and Micro-C interactions, complemented with renal-specific quantitative trait loci, to predict enhancer-gene relationships. Our analyses implicate variation in hypoxia sensing, cell cycle regulation, and telomerase maintenance pathways as central mediators of ccRCC risk. These findings provide new insights into the molecular basis of ccRCC susceptibility and highlight potential therapeutic avenues for prevention and treatment.