title: Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression.
abstract: 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.
authors.affiliation: Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK. schoedel@well.ox.ac.uk
authors.forename: Johannes
authors.initials: J
authors.lastname: Schödel
authors.forename: Chiara
authors.initials: C
authors.lastname: Bardella
authors.forename: Lina K
authors.initials: LK
authors.lastname: Sciesielski
authors.forename: Jill M
authors.initials: JM
authors.lastname: Brown
authors.forename: Chris W
authors.initials: CW
authors.lastname: Pugh
authors.forename: Veronica
authors.initials: V
authors.lastname: Buckle
authors.forename: Ian P
authors.initials: IP
authors.lastname: Tomlinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Ratcliffe
authors.forename: David R
authors.initials: DR
authors.lastname: Mole
mesh_terms: D059447:Cell Cycle Checkpoints / Q000235:genetics; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D019938:Cyclin D1 / Q000096:biosynthesis / Q000235:genetics*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C530104:CCND1 protein, human; D051793:Hypoxia-Inducible Factor 1; D019938:Cyclin D1; D051794:Von Hippel-Lindau Tumor Suppressor Protein