An RCC susceptibility locus lies within a CCND1 enhancer.

  • Major Finding: An RCC susceptibility locus lies within a CCND1 enhancer.

  • Mechanism: Polymorphism affects HIF binding and CCND1 transcription.

  • Impact: Intergenic variants may promote cancer by affecting cell type–specific enhancers.

The mechanistic contributions of susceptibility loci identified in genome-wide association studies to cancer development are often unclear, especially if the polymorphic sites are not proximal to an annotated gene. During an effort to characterize genome-wide hypoxia-inducible factor 2α (HIF-2α) localization in renal cell carcinomas (RCC), Schödel and colleagues observed that some of the strongest binding sites were in a region tightly linked to a previously identified RCC susceptibility locus at chromosome 11q13.3. This intergenic locus lacked the sequence features of a gene promoter but had the epigenetic characteristics of a transcriptional enhancer—reduced nucleosome occupancy, high levels of histone H3 lysine 4 monomethylation and lysine 27 acetylation, and low levels of trimethylated histone H3 lysine 4 and RNA polymerase II binding—specifically in RCC cells lacking the von Hippel–Landau tumor suppressor (VHL), a key negative regulator of HIF proteins that is frequently inactivated in RCC. Genome-wide expression analysis identified cyclin D1 (CCND1), an oncogene that is not only commonly upregulated in RCC but also lies 220 kb downstream of the RCC susceptibility locus, as one of the most HIF-2α–dependent genes on chromosome 11. Genotype-specific chromatin immunoprecipitation and PCR confirmed that RCC-predisposing alleles were associated with higher HIF-2α occupancy at the susceptibility locus and increased levels of CCND1 expression. Additionally, high-resolution fluorescence in situ hybridization and chromatin conformation capture (3C) indicated that the HIF-2α–bound region physically associated with the CCND1 promoter. Taken together, these findings implicate the 11q13.3 RCC susceptibility locus as a transcriptional enhancer of CCND1 and provide support for the concept that intergenic disease-associated single-nucleotide polymorphisms may be associated with cell type–specific enhancers.

Schödel J, Bardella C, Sciesielski LK, Brown JM, Pugh CW, Buckle V, et al. Common genetic variants at the 11q13.3 renal cancer susceptibility locus influence binding of HIF to an enhancer of cyclin D1 expression. Nat Genet 2012 Mar 11. [Epub ahead of print].