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

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

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Atlases as Topic
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 12 / chemistry*
  • Chromosomes, Human, Pair 12 / metabolism
  • Computational Biology
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Humans
  • Interleukin-11 / genetics*
  • Interleukin-11 / metabolism
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • Mice
  • Neoplasm Transplantation
  • Polymorphism, Single Nucleotide
  • Protein Binding
  • Transcription Factor AP-1 / genetics
  • Transcription Factor AP-1 / metabolism

Substances

  • BHLHE41 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • IL11 protein, human
  • Interleukin-11
  • Transcription Factor AP-1