Wasserman, N. F., Aneas, I. & Nobrega, M. A. An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Genome Res. 20, 1191-1197

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Genome Research (Impact Factor: 14.63). 09/2010; 20(9):1191-7. DOI: 10.1101/gr.105361.110
Source: PubMed


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.

    • "These conserved non-coding elements (CNEs) often act as cis-regulatory elements of nearby genes in specific tissues and time points, and some have already been shown to be associated with vertebrate development and transcriptional regulation (Bejerano et al. 2004;Woolfe et al. 2005;Lowe et al. 2011). In humans, a large fraction of common trait and disease variation is non-coding (Hindorff et al. 2009), and a growing number of cis-regulatory mutations have been implicated in human disease (Ragvin et al. 2010;Wasserman et al. 2010). In fact, over 80% of single-nucleotide polymorphisms (SNPs) found to be associated with diseases through genome wide association studies (GWAS) are non-coding (Hindorff et al. 2009). "
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    ABSTRACT: Evolutionary changes in cis-regulatory elements are thought to play a key role in morphological and physiological diversity across animals. Many conserved non-coding elements (CNEs) function as cis-regulatory elements, controlling gene expression levels in different biological contexts. However, determining specific associations between CNEs and related phenotypes is a challenging task. Here, we present a computational “reverse genomics” approach that predicts the phenotypic functions of human CNEs. We identify thousands of human CNEs that were lost in at least two independent mammalian lineages (IL-CNEs), and match their evolutionary profiles against a diverse set of phenotypes recently annotated across multiple mammalian species. We identify 2,759 compelling associations between human CNEs and a diverse set of mammalian phenotypes. We discuss multiple CNEs, including a predicted ear element near BMP7, a pelvic CNE in FBN1, a brain morphology element in UBE4B, and an aquatic adaptation forelimb CNE near EGR2, and provide a full list of our predictions. As more genomes are sequenced and more traits are annotated across species, we expect our method to facilitate the interpretation of non-coding mutations in human disease and expedite the discovery of individual CNEs that play key roles in human evolution and development.
    No preview · Article · Jan 2016 · Molecular Biology and Evolution
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    • "b For this SNP, major allele T is the risk allele, as previously reported [15]. breast cancer [18]. To date, studies investigating BC susceptibility focused on SNPs located within the prostate and breast cancer sub-region. "
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    ABSTRACT: Increasing evidence indicates that common genetic variants may contribute to the heritable risk of breast cancer (BC). In this study, we investigated whether single nucleotide polymorphisms (SNPs), within the 8q24.21 multi-cancer susceptibility region and within BC-associated loci widespread in the genome, may influence the risk of BC in men, and whether they may be associated with specific clinical-pathologic characteristics of male BC (MBC). In the frame of the ongoing Italian Multicenter Study on MBC, we performed a case-control study on 386 MBC cases, including 50 BRCA1/2 mutation carriers, and 1105 healthy male controls, including 197 unaffected BRCA1/2 mutation carriers. All 1491 subjects were genotyped by Sequenom iPLEX technology for a total of 29 susceptibility SNPs. By logistic regression models, we found a significant association with MBC risk for five SNPs: rs1562430 (p=0.002) and rs445114 (p=0.026) both within the 8q24.21 region; rs1011970/9p21.3 (p=0.011), rs614367/11q13.3 (p=0.016) and rs1314913/14q24.1 (p<0.0001). Differences in the distribution of rs614367/11q13.3 genotypes according to oestrogen receptor (ER) status (p=0.006), and of rs1011970/9p21.3 genotypes according to human epidermal growth factor receptor 2 (HER2) status (p=0.002) emerged. Association of rs1011970/9p21.3 risk genotype with HER2+MBC was confirmed by a multivariate analysis. rs1314913/14q24.1 was associated with increased MBC risk in analyses restricted to male BRCA1/2 mutation carriers (p=0.041). In conclusion, we provided the first evidence that the 8q24.21 region is associated with MBC risk. Furthermore, we showed that the SNPs rs1562430/8q24.21 and rs1314913/14q24.1 strongly influence BC risk in men and suggested that the SNP rs1314913/14q24.1 may act as a risk modifier locus in male BRCA1/2 mutation carriers. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Aug 2015 · European journal of cancer (Oxford, England: 1990)
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    • "In the current study, we successfully assessed 10 SNPs in 249 GC cases and 292 controls. Mechanistically, rs6983267 was hypothesized to confer risk for colorectal cancer (Pomerantz et al., 2009) and prostate cancer (Wasserman et al., 2010) by influencing MYC expression; however, negative evidence has also been reported (Olsson and Hall;). The SNP rs4444235 showed cis-acting regulation of bone morphogenetic protein 4 (BMP4) (Lubbe et al., 2012), although the relevant mechanisms remain unknown. "
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    ABSTRACT: Evidence suggests that some genetic variants are risk factors for both colorectal cancer (CRC) and gastric cancer (GC). Thus, we selected 12 reported single nucleotide polymorphisms (SNPs) from genome-wide association studies of CRC and conducted this case-control study to assess the associations between these SNPs and the risk for GC in a southern Chinese population. All SNPs were genotyped in 249 individuals with GC and 292 healthy population-matched subjects using the Sequenom MassArray iPLEX System. Association analyses based on the c2 test and binary logistic regression were performed to determine the odds ratio (OR) and 95% confidence interval (95%CI) for each SNP. A stratified analysis by gender was also performed. Borderline significant associations were observed for rs4444235 (P = 0.070) and rs10411210 (P = 0.084), both fitting the overdominant model. The rs4444235 CT genotype showed a protective effect (OR = 0.72, 95%CI = 0.50-1.03), while the rs10411210 CT genotype was a risk factor (OR = 1.40, 95%CI = 0.96-2.05) as compared with the CC+TT genotype. In the female subgroup, the rs6983267 GT genotype (compared with TT, OR = 2.31, 95%CI = 1.07-4.99) and the rs10505477 CT genotype (compared with TT, OR = 2.36, 95%CI = 1.09-5.11) significantly increased the risk for GC. No significant association was detected for the other SNPs. These results provide evidence that known genetic variants associated with CRC risk may also confer risk for GC.
    Preview · Article · May 2014 · Genetics and molecular research: GMR
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