Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression

Though genome-wide association studies (GWAS) have identified the existence of numerous population-based cancer susceptibility loci, mechanistic insights remain limited, particularly for intergenic polymorphisms. Here we show that polymorphism at a remote intergenic region on chromosome 11q13.3, recently identified as a susceptibility locus for renal cell carcinoma(1), modulates the binding and function of hypoxia inducible factor (HIF) at a previously unrecognized, transcriptional enhancer of cyclin D1 specific for renal cancers characterized by pVHL inactivation. The protective haplotype impairs binding of HIF-2 resulting in an allelic imbalance in cyclin D1 expression, thus affecting a link between hypoxia pathways and cell cycle control.