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An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Genome Research (Impact Factor: 13.85). 09/2010; 20(9):1191-7. DOI: 10.1101/gr.105361.110
Source: PubMed

ABSTRACT Genome-wide association studies (GWAS) routinely identify risk variants in noncoding DNA, as exemplified by reports of multiple single nucleotide polymorphisms (SNPs) associated with prostate cancer in five independent regions in a gene desert on 8q24. Two of these regions also have been associated with breast and colorectal cancer. These findings implicate functional variation within long-range cis-regulatory elements in disease etiology. We used an in vivo bacterial artificial chromosome (BAC) enhancer-trapping strategy in mice to scan a half-megabase of the 8q24 gene desert encompassing the prostate cancer-associated regions for long-range cis-regulatory elements. These BAC assays identified both prostate and mammary gland enhancer activities within the region. We demonstrate that the 8q24 cancer-associated variant rs6983267 lies within an in vivo prostate enhancer whose expression mimics that of the nearby MYC proto-oncogene. Additionally, we show that the cancer risk allele increases prostate enhancer activity in vivo relative to the non-risk allele. This allele-specific enhancer activity is detectable during early prostate development and throughout prostate maturation, raising the possibility that this SNP could assert its influence on prostate cancer risk before tumorigenesis occurs. Our study represents an efficient strategy to build experimentally on GWAS findings with an in vivo method for rapidly scanning large regions of noncoding DNA for functional cis-regulatory sequences harboring variation implicated in complex diseases.

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    • "To date, the majority of identified variants have been found in noncoding regions of the genome (Maurano et al., 2012). Recent evidence suggests that a subset of these variants affect transcriptional mechanisms through modulation of regulatory elements (Musunuru et al., 2010; Pomerantz et al., 2009; Smemo et al., 2012; Tuupanen et al., 2009; van den Boogaard et al., 2012; Visser et al., 2012; Wasserman et al., 2010). Based on the high modularity of regulatory elements, each regulating transcription at different time points and in different tissues, and the high frequency of variants in the population, one can expect that single-nucleotide variants will have only minor contributions to the trait or disease risk. "
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    • "In some cases, as in the association between prostate cancer and the 8q24 locus, the associated variant has a functional effect (Wasserman et al., 2010). However, for many studies the associated variant has no obvious biologic connection to the disease or trait in question, leading to the notion that the associated variant is in LD with a causal one. "
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    • "Indeed, we were able to identify promising candidates that regulate Six1 expression in the PPR (Sato et al., 2010) and the potential regulatory mechanism in the olfactory/ otic/epibranchial placodes (Fig. 5 and see below). Further analysis should enhance our understanding of the etiology of BOR and related syndromes: mutations that affect some of the identified Six1 enhancers might be causative for those disorders as described previously for mutations of SHH (Lettice et al., 2003), RET (Emison et al., 2005) and MYC (Wasserman et al., 2010). "
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