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Validation of genome-wide prostate cancer associations in men of African descent.

ABSTRACT: Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSMB, rs12418451 and rs7931342 at 11q13, and rs5945572 and rs5945619 at NUDT10/11. These associations were in the same direction and of similar magnitude as those reported in men of European descent. Significance was attained at all reported prostate cancer susceptibility regions at chromosome 8q24, including associations reaching genome-wide significance in region 2.We have validated in men of African descent the associations at some, but not all, prostate cancer susceptibility loci originally identified in European descent populations. This may be due to the heterogeneity in genetic etiology or in the pattern of genetic variation across populations.The genetic etiology of prostate cancer in men of African descent differs from that of men of European descent.

SUBMITTER: Chang BL

PROVIDER: S-EPMC3110616 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Validation of genome-wide prostate cancer associations in men of African descent.

Chang Bao-Li BL Spangler Elaine E Gallagher Stephen S Haiman Christopher A CA Henderson Brian B Isaacs William W Benford Marnita L ML Kidd LaCreis R LR Cooney Kathleen K Strom Sara S Ingles Sue Ann SA Stern Mariana C MC Corral Roman R Joshi Amit D AD Xu Jianfeng J Giri Veda N VN Rybicki Benjamin B Neslund-Dudas Christine C Kibel Adam S AS Thompson Ian M IM Leach Robin J RJ Ostrander Elaine A EA Stanford Janet L JL Witte John J Casey Graham G Eeles Rosalind R Hsing Ann W AW Chanock Stephen S Hu Jennifer J JJ John Esther M EM Park Jong J Stefflova Klara K Zeigler-Johnson Charnita C Rebbeck Timothy R TR

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20101111 1

<h4>Background</h4>Genome-wide association studies (GWAS) have identified numerous prostate cancer susceptibility alleles, but these loci have been identified primarily in men of European descent. There is limited information about the role of these loci in men of African descent.<h4>Methods</h4>We identified 7,788 prostate cancer cases and controls with genotype data for 47 GWAS-identified loci.<h4>Results</h4>We identified significant associations for SNP rs10486567 at JAZF1, rs10993994 at MSM ...[more]

PMID: 21071540

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Project description:Increasing evidence suggests that aberrant DNA methylation changes may contribute to prostate cancer (PCa) ethnic disparity. To comprehensively identify DNA methylation alterations in PCa disparity, we used the Illumina 450K methylation platform to interrogate the methylation status of 485,577 CpG sites focusing on gene-associated regions of the human genome. Genomic DNA from African-American (AA; 7 normal and 3 cancers) and Caucasian (Cau; 8 normal and 3 cancers) was used in the analysis. Hierarchical clustering analysis identified probe-sets unique to AA and Cau samples, as well as common to both. We selected 25 promoter-associated novel CpG sites most differentially methylated by race (fold change > 1.5-fold; adjusted P < 0.05) and compared the ?-value of these sites provided by the Illumina, Inc. array with quantitative methylation obtained by pyrosequencing in 7 prostate cell lines. We found very good concordance of the methylation levels between ?-value and pyrosequencing. Gene expression analysis using qRT-PCR in a subset of 8 genes after treatment with 5-aza-2'-deoxycytidine and/or trichostatin showed up-regulation of gene expression in PCa cells. Quantitative analysis of 4 genes, SNRPN, SHANK2, MST1R, and ABCG5, in matched normal and PCa tissues derived from AA and Cau PCa patients demonstrated differential promoter methylation and concomitant differences in mRNA expression in prostate tissues from AA vs. Cau. Regression analysis in normal and PCa tissues as a function of race showed significantly higher methylation prevalence for SNRPN (P = 0.012), MST1R (P = 0.038), and ABCG5 (P < 0.0002) for AA vs. Cau samples. We selected the ABCG5 and SNRPN genes and verified their biological functions by Western blot analysis and siRNA gene knockout effects on cell proliferation and invasion in 4 PCa cell lines (2 AA and 2 Cau patients-derived lines). Knockdown of either ABCG5 or SNRPN resulted in a significant decrease in both invasion and proliferation in Cau PCa cell lines but we did not observe these remarkable loss-of-function effects in AA PCa cell lines. Our study demonstrates how differential genome-wide DNA methylation levels influence gene expression and biological functions in AA and Cau PCa.

Dataset Information

Validation of genome-wide prostate cancer associations in men of African descent.

Publications

Validation of genome-wide prostate cancer associations in men of African descent.

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