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

Pierre Bigot, Leandro M. Colli, Mitchell J. Machiela, Lea Jessop, Timothy A. Myers, Julie Carrouget, Sarah Wagner, David Roberson, Caroline Eymerit, Daniel Henrion and Stephen J. Chanock ()
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Pierre Bigot: National Cancer Institute, National Institutes of Health
Leandro M. Colli: National Cancer Institute, National Institutes of Health
Mitchell J. Machiela: National Cancer Institute, National Institutes of Health
Lea Jessop: National Cancer Institute, National Institutes of Health
Timothy A. Myers: National Cancer Institute, National Institutes of Health
Julie Carrouget: Angers University Hospital
Sarah Wagner: Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc.
David Roberson: Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc.
Caroline Eymerit: Angers University Hospital
Daniel Henrion: CNRS UMR 6214, INSERM U1083, Université d'Angers, UFR de Médecine, rue haute de reculée
Stephen J. Chanock: National Cancer Institute, National Institutes of Health

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12098

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