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Nat Commun. 2016 Jul 7;7:12098. doi: 10.1038/ncomms12098.

Functional characterization of the 12p12.1 renal cancer-susceptibility locus implicates BHLHE41.

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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.
Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., 8717 Grovemont Circle, Bethesda, Maryland 20892, USA.
Department of Pathology, Angers University Hospital, 4 rue Larrey, Angers 49100, France.
CNRS UMR 6214, INSERM U1083, Université d'Angers, UFR de Médecine, rue haute de reculée, Angers 49045, France.


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.

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