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

Johannes Schödel; Chiara Bardella; Lina K Sciesielski; Jill M Brown; Chris W Pugh; Veronica Buckle; Ian P Tomlinson; Peter J Ratcliffe; David R Mole

doi:10.1038/ng.2204

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

Johannes Schödel, Chiara Bardella, Lina K Sciesielski, Jill M Brown, Chris W Pugh, Veronica Buckle, Ian P Tomlinson, Peter J Ratcliffe, David R Mole

Research output: Contribution to journal › Article › peer-review

104 Citations (Scopus)

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.

Original language	English
Pages (from-to)	420-5, S1-2
Journal	Nature Genetics
Volume	44
Issue number	4
DOIs	https://doi.org/10.1038/ng.2204
Publication status	Published - 11 Mar 2012

Keywords

Cell Cycle Checkpoints/genetics
Cell Hypoxia
Cell Line, Tumor
Chromosomes, Human, Pair 11/genetics
Cyclin D1/biosynthesis
Enhancer Elements, Genetic
Gene Expression Regulation, Neoplastic
Genetic Predisposition to Disease
Genetic Variation
Humans
Hypoxia-Inducible Factor 1/metabolism
Kidney Neoplasms/genetics
Molecular Sequence Data
Polymorphism, Single Nucleotide
Von Hippel-Lindau Tumor Suppressor Protein/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.2204

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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.",

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author = "Johannes Sch{\"o}del and Chiara Bardella and Sciesielski, {Lina K} and Brown, {Jill M} and Pugh, {Chris W} and Veronica Buckle and Tomlinson, {Ian P} and Ratcliffe, {Peter J} and Mole, {David R}",

year = "2012",

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doi = "10.1038/ng.2204",

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T1 - Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression

AU - Schödel, Johannes

AU - Bardella, Chiara

AU - Sciesielski, Lina K

AU - Brown, Jill M

AU - Pugh, Chris W

AU - Buckle, Veronica

AU - Tomlinson, Ian P

AU - Ratcliffe, Peter J

AU - Mole, David R

PY - 2012/3/11

Y1 - 2012/3/11

N2 - 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.

AB - 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.

KW - Cell Cycle Checkpoints/genetics

KW - Cell Hypoxia

KW - Cell Line, Tumor

KW - Chromosomes, Human, Pair 11/genetics

KW - Cyclin D1/biosynthesis

KW - Enhancer Elements, Genetic

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Humans

KW - Hypoxia-Inducible Factor 1/metabolism

KW - Kidney Neoplasms/genetics

KW - Molecular Sequence Data

KW - Polymorphism, Single Nucleotide

KW - Von Hippel-Lindau Tumor Suppressor Protein/genetics

U2 - 10.1038/ng.2204

DO - 10.1038/ng.2204

M3 - Article

C2 - 22406644

SN - 1061-4036

VL - 44

SP - 420-5, S1-2

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

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

Abstract

Keywords

UN SDGs

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