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.

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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.
    European journal of cancer (Oxford, England: 1990) 08/2015; 51(16). DOI:10.1016/j.ejca.2015.07.020 · 5.42 Impact Factor
    • "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. "

    34th Annual Meeting of the; 04/2014
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    • "Recent advances in the theoretical and experimental methods used to study DNA packaging within cells make it possible to elucidate the biological function and pathways to which SNPs located within gene deserts can contribute. This has been shown in a number of gene deserts, most notably: SNPs within a 1.2 Mb region on chromosome 8q24, a known gene desert, have been implicated in cancer-type-specific interactions with Myc, a highly potent cancer gene > 300 kb away (Amundadottir et al., 2006; Ghoussaini et al., 2008; Ahmadiyeh et al., 2010; Wasserman et al., 2010). This same region has also been implicated in pediatric asthma in an Asian population (Noguchi et al., 2011) and non-syndromic cleft lip in pediatric patients (Grant et al., 2009). "
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    ABSTRACT: Genome wide association studies are central to the evolution of personalized medicine. However, the propensity for single nucleotide polymorphisms (SNPs) to fall outside of genes means that understanding how these polymorphisms alter cellular function requires an expanded view of human genetics. Integrating the study of genome structure (chromosome conformation capture) into its function opens up new avenues of exploration. Changes in the epigenome associated with SNPs in gene deserts will allow us to define complex diseases in a much clearer manner, and usher in a new era of disease pathway exploration.
    Frontiers in Genetics 02/2014; 5:39. DOI:10.3389/fgene.2014.00039
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