Chromosome 8q24 is an established risk locus for many common epithelial cancers. The region was originally discovered by fine-mapping of a prostate cancer linkage peak from a family-based study by deCODE genetics 
and common alleles in the region have subsequently been found in genome-wide scans of prostate, colon and breast cancer 
. More recently, several other cancer types were associated with different discrete regions of 8q24, with the exception of rs6983267, which is a susceptibility marker for prostate and colon cancers, and perhaps also ovarian and other cancers 
. The alleles reside in distinct linkage disequilibrium blocks including three independent regions for prostate cancer risk (regions 1–3), one for breast cancer risk and one for bladder cancer risk 
. These findings suggest that a common biological mechanism underlies the association of cancer with 8q24 polymorphisms, and also argue for organ- and site-specific functions of elements in this region. Most of the cancer risk variants at 8q24 are encompassed in an approximately 500-kb long stretch of sequence that is devoid of well-characterized genes - the closest annotated gene locus in this area is the oncogene MYC that resides approximately 200-kb telomeric from the nearest linkage disequilibrium block region containing a risk variant.
Since the consequences of sequence changes in non protein-coding regions of the genome are more difficult to predict than changes in coding regions, defining the mechanisms by which the 8q24 alleles confer risk has so far been challenging. Another complication is that genetic variants discovered through association studies are rarely the actual causal variant, since they may be associated with disease risk simply due to linkage disequilibrium, which sometimes extends over relatively large distances in the human genome. Because of these factors, understanding the mechanisms that increase cancer risk requires an integrated and systematic approach. One hypothesis is that the 8q24 alleles affect the sequence of unannotated transcripts (e.g. noncoding RNAs or unknown protein-coding genes) or change the regulation of such transcripts in cis
. The ENCODE project and the recent reports on long noncoding RNAs 
clearly demonstrated that a large number of unannotated transcripts are expressed in the human genome 
. Another hypothesis is that the 8q24 risk regions contain specialized and perhaps tissue-specific regulatory elements (enhancers) that can influence the behavior of other loci (i.e. their target genes).
Post-translational modifications of histones (e.g. methylation, acetylation, etc.) have proven useful in annotating sites of regulatory activity in the human genome. Histone 3 acetylation (AcH3) is typically associated with chromatin accessibility and transcriptional activity, and widely used for the prediction of functional elements such as promoters and enhancers 
. Studies further demonstrate that other histone modifications [e.g., mono- and tri-methylation at histone 3 lysine 4 (H3K4me1 & 3, respectively) and trimethylation at histone 3 lysines 27 and 36 (H3K27me3 & H3K36me3, respectively)] are strongly correlated with different modes of genomic activity. Specifically, H3K4me3 is often associated with active transcription start sites (TSSs), H3K4me1 with enhancers and regions flanking TSSs, H3K27me3 with transcriptional silencing and H3K36me3 with transcriptional elongation through genes 
. Loci that are mapped as putatively active based on epigenomic profiling can then be independently evaluated through functional analyses, such as reporter assays 
The overall objective of this study was to systematically evaluate the possible role(s) of regions within the 8q24 genomic risk interval, overcoming the aforementioned difficulties using a combination of epigenetic, bioinformatic, and molecular biological analyses on multiple cell lines and tissue samples. We report here two main findings: (i) evidence is presented that certain 8q24 risk regions exhibit minimal RNA transcriptional output but bear the markers of regulatory elements that are functionally active as enhancers. (ii) More specifically, we demonstrate that a new androgen-dependent enhancer in one of the prostate cancer risk regions is functionally influenced by a risk-associated single nucleotide polymorphism (SNP) via differential FoxA1 binding.