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PMID: 22406644 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature genetics ·Vol. 44 ·No. 4 ·2012-03-11 ·Pages 420-5, S1-2

Schödel J, Bardella C, Sciesielski LK, Brown JM, Pugh CW, Buckle V, Tomlinson IP, Ratcliffe PJ, Mole DR

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.

MeSH Terms
Cell Cycle Checkpoints/genetics Cell Hypoxia Cell Line, Tumor Chromosomes, Human, Pair 11/genetics Cyclin D1/biosynthesis,genetics Enhancer Elements, Genetic Gene Expression Regulation, Neoplastic Genetic Predisposition to Disease Genetic Variation Humans Hypoxia-Inducible Factor 1/metabolism Kidney Neoplasms/genetics,metabolism Molecular Sequence Data Polymorphism, Single Nucleotide Von Hippel-Lindau Tumor Suppressor Protein/genetics,metabolism
Chemicals
CCND1 protein, human Hypoxia-Inducible Factor 1 Cyclin D1 Von Hippel-Lindau Tumor Suppressor Protein
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Schödel Johannes
Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK. [email protected]
Bardella Chiara
Sciesielski Lina K
Brown Jill M
Pugh Chris W
Buckle Veronica
Tomlinson Ian P
Ratcliffe Peter J
Mole David R
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.2204
Email
[email protected]
Published
2012-03-11
Epub
2012-00-11
Pages
420-5, S1-2
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC3378637
Subset
IM
Grants
Wellcome Trust · 078333/Z/05/Z · United Kingdom
Wellcome Trust · 078333 · United Kingdom
Wellcome Trust · 088182/Z/09/Z · United Kingdom
Wellcome Trust · 091857 · United Kingdom
Medical Research Council · MC_UU_12009/1 · United Kingdom
Wellcome Trust · 088182 · United Kingdom
Cancer Research UK · A4285 · United Kingdom
Wellcome Trust · 090532 · United Kingdom
Wellcome Trust · WT091857MA · United Kingdom
Databases
GEO
GSE28352, GSE34871
Corrections
CommentIn
PMID: 22495323
External Links
PubMed source DOI: 10.1038/ng.2204 PMC Full Text View journal details
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