title: Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.
abstract: Genome-wide association studies have identified multiple renal cell carcinoma (RCC) susceptibility loci. Here, we use regional imputation and bioinformatics analysis of the 12p12.1 locus to identify the single-nucleotide polymorphism (SNP) rs7132434 as a potential functional variant. Luciferase assays demonstrate allele-specific regulatory activity and, together with data from electromobility shift assays, suggest allele-specific differences at rs7132434 for AP-1 transcription factor binding. In an analysis of The Cancer Genome Atlas data, SNPs highly correlated with rs7132434 show allele-specific differences in BHLHE41 expression (trend P value=6.3 × 10(-7)). Cells overexpressing BHLHE41 produce larger mouse xenograft tumours, while RNA-seq analysis reveals that constitutively increased BHLHE41 induces expression of IL-11. We conclude that the RCC risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.|Department of Urology, Angers University Hospital, 4 rue Larrey, Angers 49100, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Bigot
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Leandro M
authors.initials: LM
authors.lastname: Colli
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Mitchell J
authors.identifier: 0000-0001-6538-9705
authors.initials: MJ
authors.lastname: Machiela
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Lea
authors.initials: L
authors.lastname: Jessop
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Myers
authors.affiliation: Department of Urology, Angers University Hospital, 4 rue Larrey, Angers 49100, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Carrouget
authors.affiliation: Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Wagner
authors.affiliation: Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: David
authors.initials: D
authors.lastname: Roberson
authors.affiliation: Department of Pathology, Angers University Hospital, 4 rue Larrey, Angers 49100, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Eymerit
authors.affiliation: CNRS UMR 6214, INSERM U1083, Université d'Angers, UFR de Médecine, rue haute de reculée, Angers 49045, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Chanock
mesh_terms: D000483:Alleles; D000818:Animals; D001271:Atlases as Topic; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002881:Chromosomes, Human, Pair 12 / Q000737:chemistry* / Q000378:metabolism; D019295:Computational Biology; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D017370:Interleukin-11 / Q000235:genetics* / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009368:Neoplasm Transplantation; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017370:Interleukin-11; D018808:Transcription Factor AP-1; C422085:BHLHE41 protein, human; C508611:IL11 protein, human