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

Nature Genetics volume 44, pages 420–425 (2012)Cite this article

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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 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.

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Figure 1: HIF binding at 11q13.3.
Figure 2: Chromatin structure and function of an enhancer at 11q13.3.
Figure 3: Cell type specificity of the 11q13.3 enhancer.
Figure 4: Physical association of the remote HIF-binding site with the CCND1 promoter.
Figure 5: The minor (RCC-protective) allele at 11q13.3 disrupts HIF binding and enhancer activity.

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Acknowledgements

Samples of renal tumors were a gift from A.L. Harris through the Oxford Radcliffe Biobank, Oxford Biomedical Research Centre. HKC-8 cells were provided by L. Racusen (Johns Hopkins University), 786-O cells re-expressing pVHL were a gift from W.G. Kaelin Jr. (Harvard Medical School), RCC4 cells were a gift from C.H. Buys (University of Groningen), and all other RCC cells were from M. Lerman (National Institutes of Health). This work was funded by the Wellcome Trust (088182/Z/09/Z, 078333/Z/05/Z and WT091857MA to J.S.), the Higher Education Funding Council for England, the German Research Foundation (SC 132/2-1 to L.K.S.) and by Urology Cancer Research and Education (UCARE).

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Authors and Affiliations

  1. Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK

    Johannes Schödel, Lina K Sciesielski, Chris W Pugh, Peter J Ratcliffe & David R Mole

  2. Molecular and Population Genetics Laboratory, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Chiara Bardella & Ian P Tomlinson

  3. Weatherall Institute of Molecular Medicine, John Radcliffe Hospital and University of Oxford, Oxford, UK

    Jill M Brown & Veronica Buckle

  4. Oxford National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    Ian P Tomlinson

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Schödel, J., Bardella, C., Sciesielski, L. et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat Genet 44, 420–425 (2012). https://doi.org/10.1038/ng.2204

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