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

Abstract

Johannes Schödel and colleagues report the identification of a distant transcriptional enhancer of CCND1 at the recently identified renal cell carcinoma susceptibility locus at 11q13.3. The protective haplotype shows reduced binding of HIF-2α, reduced interaction with the transcriptional machinery and allelic imbalance in CCND1 expression. The study suggests that the hypoxia pathway is misregulated in renal cell carcinoma development. Although 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 carcinoma1, modulates the binding and function of hypoxia-inducible factor (HIF) at a previously unrecognized transcriptional enhancer of CCND1 (encoding cyclin D1) that is specific for renal cancers characterized by inactivation of the von Hippel–Lindau tumor suppressor (pVHL). 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.