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 carcinoma, 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.
Journal article
2012-03-11T00:00:00+00:00
44
420 - S2
Cell Cycle Checkpoints, Cell Hypoxia, Cell Line, Tumor, Chromosomes, Human, Pair 11, Cyclin D1, Enhancer Elements, Genetic, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genetic Variation, Humans, Hypoxia-Inducible Factor 1, Kidney Neoplasms, Molecular Sequence Data, Polymorphism, Single Nucleotide, Von Hippel-Lindau Tumor Suppressor Protein