Genetic polymorphism and prostate cancer aggressiveness: A case-only study of 1,536 GWAS and candidate SNPs in African-Americans and European-Americans

Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
The Prostate (Impact Factor: 3.57). 01/2013; 73(1). DOI: 10.1002/pros.22532
Source: PubMed


BACKGROUND: Genome-wide association studies have established a number of replicated single nucleotide polymorphisms (SNPs) for susceptibility to prostate cancer (CaP), but it is unclear whether these susceptibility SNPs are also associated with disease aggressiveness. This study evaluates whether such replication SNPs or other candidate SNPs are associated with CaP aggressiveness in African-American (AA) and European-American (EA) men. METHODS: A 1,536 SNP panel which included 34 genome-wide association study (GWAS) replication SNPs, 38 flanking SNPs, a set of ancestry informative markers, and SNPs in candidate genes and other areas was genotyped in 1,060 AA and 1,087 EA men with incident CaP from the North Carolina-Louisiana Prostate Cancer Project (PCaP). Tests for association were conducted using ordinal logistic regression with a log-additive genotype model and a 3-category CaP aggressiveness variable. RESULTS: Four GWAS replication SNPs (rs2660753, rs13254738, rs10090154, rs2735839) and seven flanking SNPs were associated with CaP aggressiveness (P < 0.05) in three genomic regions: One at 3p12 (EA), seven at 8q24 (5 AA, 2 EA), and three at 19q13 at the kallilkrein-related peptidase 3 (KLK3) locus (two AA, one AA and EA). The KLK3 SNPs also were associated with serum prostate-specific antigen (PSA) levels in AA (P < 0.001) but not in EA. A number of the other SNPs showed some evidence of association but none met study-wide significance levels after adjusting for multiple comparisons. CONCLUSIONS: Some replicated GWAS susceptibility SNPs may play a role in CaP aggressiveness. However, like susceptibility, these associations are not consistent between racial groups. Prostate © 2012 Wiley Periodicals, Inc.

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    • "There is a wealth of evidence implicating 8q24 variant alleles in the development of CaP; some of which state that there is a higher frequency amongst those of African ancestry [42] and with earlier time to prostate cancer [43]. There are several other CaP susceptibility loci identified through genome-wide association studies, with inconsistencies between ethnic groups [44]. "
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    ABSTRACT: There is a wealth of evidence which can be traced back to the African transatlantic slave trade indicating that black men have a higher risk of prostate cancer compared to other ethnic groups. Migration to Westernised countries may have had little effect on the incidence of prostate cancer in this ethnic group; however, current evidence indicates that there are several complex factors that may contribute to this risk. Studies in the UK quote that black men are at 2–3 times the risk of prostate cancer in comparison to their Caucasian counterparts, with a 30% higher mortality rate. Caution should be taken prior to the interpretation of these results due to a paucity of research in this area, limited accurate ethnicity data, and lack of age-specific standardisation for comparison. Cultural attitudes towards prostate cancer and health care in general may have a significant impact on these figures, combined with other clinico-pathological associations. This update summarises new contributory research on this subject, highlighting the need to increase awareness and understanding of prostate cancer amongst high-risk communities and to support further robust research in this area by nominating a lead in cancer and ethnicity studies within the National Health Service.
    ecancermedicalscience 08/2014; 8:455. DOI:10.3332/ecancer.2014.455 · 1.20 Impact Factor
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    • "This study confirmed the finding of other studies showing a highly diverse proportion of European ancestry in self-identified AAs (7–21%) [9,22,23,30,32,33]. This diversity can be explained in part by the historical ‘one-drop rule’ (which classified individuals with any level of African ancestry as ‘African Americans’). "
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    ABSTRACT: This study was designed to determine the ancestral composition of a multi-ethnic sample collected for studies of drug addictions in New York City and Las Vegas, and to examine the reliability of self-identified ethnicity and three-generation family history data. Ancestry biographical scores for seven clusters corresponding to world major geographical regions were obtained using STRUCTURE, based on genotypes of 168 ancestry informative markers (AIMs), for a sample of 1,291 African Americans (AA), European Americans (EA), and Hispanic Americans (HA) along with data from 1,051 HGDP-CEPH 'diversity panel' as a reference. Self-identified ethnicity and family history data, obtained in an interview, were accurate in identifying the individual major ancestry in the AA and the EA samples (approximately 99% and 95%, respectively) but were not useful for the HA sample and could not predict the extent of admixture in any group. The mean proportions of the combined clusters corresponding to European and Middle Eastern populations in the AA sample, revealed by AIMs analysis, were 0.13. The HA subjects, predominantly Puerto Ricans, showed a highly variable hybrid contribution pattern of clusters corresponding to Europe (0.27), Middle East (0.27), Africa (0.20), and Central Asia (0.14). The effect of admixture on allele frequencies is demonstrated for two single-nucleotide polymorphisms (118A > G, 17 C > T) of the mu opioid receptor gene (OPRM1). This study reiterates the importance of AIMs in defining ancestry, especially in admixed populations.
    Human genomics 07/2012; 6(1):2. DOI:10.1186/1479-7364-6-2 · 2.15 Impact Factor
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    ABSTRACT: Inflammation has been implicated in prostate cancer (PCa) pathogenesis. Promoter DNA variants responsible for differential expression of key cytokines may therefore influence susceptibility to PCa. Two interleukin-6 (IL-6) promoter variants, -174G>C and -6331T>C, were genotyped for association with PCa risk and survival using the Risk Factors for Prostate Cancer Study (RFPCS, 825 cases and 732 controls) and the Melbourne Collaborative Cohort Study (MCCS, 818 cases and 1,745 controls). Impact of genotypes on IL-6 transcriptional activity was measured using Low Density Arrays. A significant increase in IL-6 transcriptional activity in malignant compared to benign prostate tissue supports a role for IL-6 in PCa. The -174G>C variant showed no association with PCa risk, overall survival, or IL-6 transcriptional activity. The -6331 C-allele was significantly associated with an increased risk in the RFPCS (OR = 1.29, 95% CI = 1.08-1.54), but not in the MCCS. In the MCCS however, cases presenting with a CC genotype conferred a higher risk of mortality (HR = 2.27, 95% CI = 1.34-3.85), which was maintained although reduced overall in the pooled analysis with RFPCS (HR = 1.68, 95% CI = 1.10-2.54). Furthermore, we associate the minor C-allele with a significant decrease in IL-6 transcriptional activity. While our study refutes a role for IL-6 -174G>C, it is the first to implicate -6331T>C with PCa risk and poor survival. Our observation that -6331T>C has a significant impact on IL-6 transcriptional activity, calls for further investigations into the role of this variant as a novel PCa biomarker. Prostate 72:1701-1707, 2012. © 2012 Wiley Periodicals, Inc.
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