Yeager, M., Orr, N., Hayes, R. B., Jacobs, K. B., Kraft, P., Wacholder, S. et al. Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat. Genet. 39, 645-649

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands
Nature Genetics (Impact Factor: 29.35). 05/2007; 39(5):645-9. DOI: 10.1038/ng2022
Source: PubMed


Recently, common variants on human chromosome 8q24 were found to be associated with prostate cancer risk. While conducting a genome-wide association study in the Cancer Genetic Markers of Susceptibility project with 550,000 SNPs in a nested case-control study (1,172 cases and 1,157 controls of European origin), we identified a new association at 8q24 with an independent effect on prostate cancer susceptibility. The most significant signal is 70 kb centromeric to the previously reported SNP, rs1447295, but shows little evidence of linkage disequilibrium with it. A combined analysis with four additional studies (total: 4,296 cases and 4,299 controls) confirms association with prostate cancer for rs6983267 in the centromeric locus (P = 9.42 x 10(-13); heterozygote odds ratio (OR): 1.26, 95% confidence interval (c.i.): 1.13-1.41; homozygote OR: 1.58, 95% c.i.: 1.40-1.78). Each SNP remained significant in a joint analysis after adjusting for the other (rs1447295 P = 1.41 x 10(-11); rs6983267 P = 6.62 x 10(-10)). These observations, combined with compelling evidence for a recombination hotspot between the two markers, indicate the presence of at least two independent loci within 8q24 that contribute to prostate cancer in men of European ancestry. We estimate that the population attributable risk of the new locus, marked by rs6983267, is higher than the locus marked by rs1447295 (21% versus 9%).

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    • "The recent genome-wide association studies have identified multiple genetic variants in over 40 loci that are significantly associated with a risk of prostate cancer [4]. Originally, these variants were mainly found in altogether five chromosomal regions; three independent regions of 8q24, in one region of 17q12, and one region of 17q24.3[5]–[9]. However, it has been reported that a family history is predictive for the risk of prostate cancer independently of the effect of SNPs in the risk associated chromosomal regions [1]. "
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    ABSTRACT: Understanding the impact of multiple genetic variants and their interactions on the disease penetrance of familial multiple prostate cancer is very relevant to the overall understanding of carcinogenesis. We assessed the joint effect of two loci on rs4242382 at 8q24 and rs10486567 at 7p15.2 to this end. We analyzed the data from a Finnish family-based genetic study, which was composed of 947 men including 228 cases in 75 families, to evaluate the respective effects of the two loci on the disease penetrance; in particular, the occurrence and number of prostate cancer cases within a family were utilized to evaluate the interactions between the two loci under the additive and multiplicative Poisson regression models. The risk alleles A at rs4242382 (OR = 1.14, 95% CI 1.08-1.19, P<0.0001) and a risk allele A at rs10486567 (OR = 1.06, 96%CI 1.01-1.11, P = 0.0208) were found to be associated with an increased risk of familial PrCa, especially with four or more cases within a family. A multiplicative model fitted the joint effect better than an additive model (likelihood ratio test X(2) = 13.89, P<0.0001). The influence of the risk allele A at rs10486567 was higher in the presence of the risk allele A at rs4242382 (OR = 1.09 (1.01-1.18) vs. 1.01 (0.95-1.07)). Similar findings were observed in non-aggressive PrCa, but not in aggressive PrCa. We demonstrated that two loci (rs4242382 and rs10486567) are highly associated with familial multiple PrCa, and the gene-gene interaction or statistical epistasis was consistent with the Fisher's multiplicative model. These loci's association and epistasis were observed for non-aggressive but not for aggressive tumors. The proposed statistical model can be further developed to accommodate multi-loci interactions to provide further insights into epistasis.
    Full-text · Article · Feb 2014 · PLoS ONE
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    • "Our SNP annotation and eQTL analysis showed that 1154 of the 1828 SNPs had been functionally interpreted with corresponding genes. We found that these 1154 SNPs were distributed in 40 SNP blocks, which was listed in Additional file 7. 8q24 has long been confirmed as a susceptible locus of PCa [9,12-14,61]. In our study, it was obvious that more SNPs (265) were located on chromosome 8 (chr8), compared to chr10 (185), chr4 (180), chr17 (157), chr2 (118), and chr3 (112), indicating that regulatory regions in chr8 might be more sensitive and critical in prostate cancer. "
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    ABSTRACT: Over the last decade, genome-wide association studies (GWAS) have discovered many risk associated single nucleotide polymorphisms (SNPs) of prostate cancer (PCa). However, the majority of the associated PCa SNPs, including those in linkage disequilibrium (LD) blocks, are generally not located in protein coding regions. The systematical investigation of the functional roles of these SNPs, especially the non-coding SNPs, becomes very necessary and helpful to the understanding of the molecular mechanism of PCa. In this work, we proposed a comprehensive framework at network level to integrate the SNP annotation, target gene assignment, gene ontology (GO) classification, pathway enrichment analysis and regulatory network reconstruction to illustrate the molecular functions of PCa associated SNPs. By LD expansion, we first identified 1828 LD SNPs using 49 reported GWAS SNPs as a start. We carefully annotated these 1828 LD SNPs via either UCSC known genes, UCSC regulation elements, or expression Quantitative Trait Loci (eQTL) data. As a result, we found 1154 SNPs were functionally annotated and obtained 205 unique PCa genes for further enrichment analysis. The enriched GO biological processes and pathways were found mainly related to regulation of cell death, apoptosis, cell proliferation, and metabolic process, which have been proved essential to cancer development. We constructed PCa genes specific transcription regulatory networks, finding several important genetic regulators for PCa, such as IGF-1/IGF-2 receptors, SP1, CREB1, and androgen receptor (AR). A comprehensive framework was proposed for integrative and systematic analysis of PCa SNPs, the analysis can provide essential information for the understanding of the regulatory function of GWAS SNPs in PCa, and will facilitate the discovery of novel candidate biomarkers for diagnosis and prognosis of PCa.
    Full-text · Article · Dec 2013 · BMC Genomics
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    • "Recent genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) associated with PCa risk (Duggan et al., 2007; Gudmundsson et al., 2007; Yeager et al., 2007; Gudmundsson et al., 2008; Thomas et al., 2008; Gudmundsson et al., 2009; Yeager et al., 2009; Schumacher et al., 2011). Confirmation of these risk loci among European descent has been reported extensively. "
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    ABSTRACT: Background: KLK3 gene products, like human prostate-specific antigen (PSA), are important biomarkers in the clinical diagnosis of prostate cancer (PCa). G protein-coupled receptor RFX6, C2orf43 and FOXP4 signaling plays important roles in the development of PCa. However, associations of these genes with PCa in northern Chinese men remain to be detailed. This study aimed to investigate their impact on occurrence and level of malignancy. Methods: All subjects were from Beijing and Tianjin, including 266 cases with prostate cancer and 288 normal individuals as controls. We evaluated associations between clinical covariates (age at diagnosis, prostate specific antigen, Gleason score, tumor stage and aggressive) and 6 candidate PCa risk loci, genotyped by PCR- high resolution melting curve and sequencing methods. Results: Case-control analysis of allelic frequency of PCa associated with PCa showed that one of the 6 candidate risk loci, rs339331 in the RFX6 gene, was associated with reduced risk of prostate cancer (odds ratio (OR) = 0.73, 95% confidence interval (CI) =0.57-0.94, P = 0.013) in northern Chinese men. In addition, subjects with CX (CC+TC) genotypes had a decreased risk for prostrate cancer compared to those carrying the TT homozygote (OR =0.64, 95% CI = 0.45- 0.90, P = 0.008). The TT genotype of 13q22 (rs9600079, T) was associated with tumor stage (P=0.044, OR=2.34, 95% CI=0.94-5.87). Other SNPs were not significantly associated with clinical covariates in prostate cancer (P > 0.05). CONCLUSIONS. rs339331 in the RFX6 gene may be associated with prostate cancer as a susceptibility locus in northern Chinese men.
    Full-text · Article · May 2013 · Asian Pacific journal of cancer prevention: APJCP
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