Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus

Li, Jia; Landan, Gilad; Pomerantz, Mark; Jaschek, Rami; Herman, Paula; Reich, David; Yan, Chunli; Khalid, Omar; Kantoff, Philip W.; Oh, William K.; Manak, J. Robert; Berman, Benjamin P.; Henderson, Brian E.; Frenkel, Baruch; Haiman, Christopher A.; Freedman, Matthew L.; Tanay, Amos; Coetzee, Gerhard A.

doi:10.1371/journal.pgen.1000597

Cited by 218 publications

(227 citation statements)

References 29 publications

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“…Although predicting functional consequences of non-protein coding SNPs proves challenging, loci have been identified in a GWAS in gene deserts and have been found to have functional significance in complex diseases (Jia et al 2009). SNP rs10497394 was found to regulate expression of LDLR on chromosome 19 using SCAN: SNP and CNV annotation database.…”

Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

Allen

Chen

Weeks

et al. 2013

JARO

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Chronic otitis media with effusion (COME) and recurrent otitis media (ROM) have been shown to be heritable, but candidate gene and linkage studies to date have been equivocal. Our aim was to identify genetic susceptibility factors using a genome-wide association study (GWAS). We genotyped 602 subjects from 143 families with 373 COME/ROM subjects using the Illumina Human CNV370-Duo DNA Bead Chip (324,748 SNPs). We carried out the GWAS scan and imputed SNPs at the regions with the most significant associations. Replication genotyping in an independent family-based sample was conducted for 53 SNPs: the 41 most significant SNPs with PG10 −4 and 12 imputed SNPs with PG10 −4 on chromosome 15 (near the strongest signal). We replicated the association of rs10497394 (GWAS discovery P= 1.30×10 −5 ) on chromosome 2 in the independent otitis media population (P=4.7×10 −5 ; meta-analysis P= 1.52×10 −8 ). Three additional SNPs had replication PvaluesG0.10. Two were on chromosome 15q26.1 including rs1110060, the strongest association with COME/ROM in the primary GWAS (P=3.4×10 −7 ) in KIF7 intron 7 (P=0.072), and rs10775247, a nonsynonymous SNP in TICRR exon 2 (P=0.075). The third SNP rs386057 was on chromosome 5 in TPPP intron 1 (P=0.045). We have performed the first GWAS of COME/ROM and have identified a SNP rs10497394 on chromosome 2 is significantly associated with COME/ROM susceptibility. This SNP is within a 537 kb intergenic region, bordered by CDCA7 and SP3. The genomic and functional significance of this newly identified locus in COME/ROM pathogenesis requires additional investigation.

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Section: Discussionmentioning

confidence: 99%

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

Allen

Chen

Weeks

et al. 2013

JARO

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“…Several lines of evidence suggest that elements other than MYC-335 also function in tissue-specific gene regulation. A comprehensive epigenetic mapping analysis has identified several enhancer elements within the risk loci that show tissue-specific activity both in vitro and in vivo (22,23). Apart from the rs6983267, another regulatory SNP has been identified in the enhancers, namely rs11986220, which is strongly correlated with prostate cancer predisposition SNP rs10090154 (2).…”

Section: Normal Functions Of the Regulatory Elements At 8q24mentioning

confidence: 99%

“…Apart from the rs6983267, another regulatory SNP has been identified in the enhancers, namely rs11986220, which is strongly correlated with prostate cancer predisposition SNP rs10090154 (2). It affects a FoxA1 binding site within an androgen-responsive enhancer at PrCa-1 region (22). Furthermore, the enhancer elements at 8q24 are coupled to MYC via long-range interactions in a tissue-specific manner.…”

Section: Normal Functions Of the Regulatory Elements At 8q24mentioning

confidence: 99%

Lessons from Functional Analysis of Genome-Wide Association Studies

Sur

Tuupanen²,

Whitington

et al. 2013

Cancer Research

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Most cancer-associated single-nucleotide polymorphisms (SNP) identified using genome-wide association studies are located outside of protein-coding regions, and their significance and mode of action have been a source of continuing debate. One proposed mechanism of action of the SNPs is that they would affect the activity of enhancer elements regulating critical target genes. In this review, we summarize recent results that substantiate this model. These studies have identified a cancer-specific enhancer element at the 8q24 gene desert that controls the expression of the MYC oncogene. We further discuss implications of the observed difference between normal growth control and cancer for drug development, and the inherent features of genome-wide association studies that may specifically lead to identification of disease-specific regulatory elements.

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“…The region has been extensively studied and is relatively gene-poor. A number of functional enhancers have been identified in the region 70,71 and some of these enhancers have been shown to regulate MYC.…”

Section: Discussionmentioning

confidence: 99%

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

et al. 2012

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Prostate cancer (PrCa) is the most common male cancer in developed countries and the second most common cause of cancer death after lung cancer. We recently reported a genome-wide linkage scan in 69 Finnish hereditary PrCa (HPC) families, which replicated the HPC9 locus on 17q21-q22 and identified a locus on 2q37. The aim of this study was to identify and to detect other loci linked to HPC. Here we used ordered subset analysis (OSA), conditioned on nonparametric linkage to these loci to detect other loci linked to HPC in subsets of families, but not the overall sample. We analyzed the families based on their evidence for linkage to chromosome 2, chromosome 17 and a maximum score using the strongest evidence of linkage from either of the two loci. Significant linkage to a 5-cM linkage interval with a peak OSA nonparametric allele-sharing LOD score of 4.876 on Xq26.3-q27 (DLOD ¼ 3.193, empirical P ¼ 0.009) was observed in a subset of 41 families weakly linked to 2q37, overlapping the HPCX1 locus. Two peaks that were novel to the analysis combining linkage evidence from both primary loci were identified; 18q12.1-q12.2 (OSA LOD ¼ 2.541, DLOD ¼ 1.651, P ¼ 0.03) and 22q11.1-q11.21 (OSA LOD ¼ 2.395, DLOD ¼ 2.36, P ¼ 0.006), which is close to HPC6. Using OSA allows us to find additional loci linked to HPC in subsets of families, and underlines the complex genetic heterogeneity of HPC even in highly aggregated families.

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Functional Enhancers at the Gene-Poor 8q24 Cancer-Linked Locus

Cited by 218 publications

References 29 publications

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

A Genome-Wide Association Study of Chronic Otitis Media with Effusion and Recurrent Otitis Media Identifies a Novel Susceptibility Locus on Chromosome 2

Lessons from Functional Analysis of Genome-Wide Association Studies

Genetic heterogeneity in Finnish hereditary prostate cancer using ordered subset analysis

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