Article

Single and Multigenic Analysis of the Association between Variants in 12 Steroid Hormone Metabolism Genes and Risk of Prostate Cancer

Department of Cellular and Structural Biology, The University of Texas Health Science Center, San Antonio, Texas 78229-3900, USA.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.32). 06/2009; 18(6):1869-80. DOI: 10.1158/1055-9965.EPI-09-0076
Source: PubMed

ABSTRACT To estimate the prostate cancer risk conferred by individual single nucleotide polymorphisms (SNPs), SNP-SNP interactions, and/or cumulative SNP effects, we evaluated the association between prostate cancer risk and the genetic variants of 12 key genes within the steroid hormone pathway (CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1). A total of 116 tagged SNPs covering the group of genes were analyzed in 2,452 samples (886 cases and 1,566 controls) in three ethnic/racial groups. Several SNPs within CYP19 were significantly associated with prostate cancer in all three ethnicities (P = 0.001-0.009). Genetic variants within HSD3B2 and CYP24A1 conferred increased risk of prostate cancer in non-Hispanic or Hispanic Caucasians. A significant gene-dosage effect for increasing numbers of potential high-risk genotypes was found in non-Hispanic and Hispanic Caucasians. Higher-order interactions showed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = 0.001). In African Americans, a 10-locus model, with SNPs located within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1, showed a significant interaction (P = 0.014). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < 0.001). These data are consistent with a polygenic model of prostate cancer, indicating that multiple interacting genes of the steroid hormone pathway confer increased risk of prostate cancer.

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    • "Mixed A119S , L432V Sobti et al . 2006 India 100 100 Asian L432V Cussenot et al . 2007 French 1053 837 Caucasian L432V Berndt et al . 2007 USA 488 617 Mixed R48G , L432V , N453S Beuten et al . 2008 USA 153 240 Hispanic Caucasian 213C / T . R48G , L432V , N453S Beuten et al . 2008 USA 496 498 Non - Hispanic Caucasian 213C / T . R48G , L432V , N453S Beuten et al . 2009 USA 67 133 African American R48G Rodrigues et al . 2011 Brazil 154 154 Caucasian A119S Catsburg et al . 2012 USA 1419 756 Mixed L432V Holt et al . 2013 USA 1304 1266 Caucasian L432V doi : 10 . 1371 / journal . pone . 0068634 . t001"
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    ABSTRACT: Studies investigating the association between single-nucleotide polymorphisms (SNPs) of the cytochrome P450 1B1 (CYP1B1) and prostate cancer (PCa) risk report conflicting results. To derive a more precise estimation of the relationship between CYP1B1 polymorphisms and PCa risk, a meta-analysis was performed. A comprehensive literature search was conducted to identify all eligible studies of CYP1B1 polymorphisms and PCa risk. A total of 14 independent studies, including 6380 cases and 5807 controls, were identified. We investigated by meta-analysis the effects of 5 polymorphisms in CYP1B1 L432V (12 studies, 5999 cases, 5438 controls), R48G (6 studies, 1647 cases, 1846 controls), N453S (4 studies, 1407 cases, 1499 controls), -13C/T (4 studies, 1116 cases, 1114 controls), and A119S (4 studies, 1057 cases, 1018 controls). There was no evidence that L432V had significant association with PCa in overall population. After subgroup analyses by ethnicity, we found that L432V was significantly associated with PCa risk in Asians (additive: OR = 2.38, 95%CI = 1.31-4.33, P = 0.004; recessive: OR = 2.11, 95%CI = 1.17-3.79, P = 0.01; dominant: OR = 1.52, 95%CI = 1.14-2.01, P = 0.004; allelic: OR = 1.52, 95%CI = 1.20-1.92, P = 0.0006). When stratified by source of controls, significantly elevated PCa risk was found in all genetic models in population based studies (additive: OR = 1.34, 95%CI = 1.14-1.57, P = 0.0003; recessive: OR = 1.25, 95%CI = 1.09-1.43, P = 0.002; dominant: OR = 1.25, 95%CI = 1.11-1.41, P = 0.0002; allelic: OR = 1.18, 95%CI = 1.09-1.28, P<0.0001). For N453S, there was a significant association between N453S polymorphism and PCa risk in both overall population (dominant: OR = 1.18, 95%CI = 1.00-1.38, P = 0.04) and mixed population (domiant: OR = 1.31, 95%CI = 1.06-1.63, P = 0.01; allelic: OR = 1.27, 95%CI = 1.05-1.54, P = 0.01). For A119S, our analysis suggested that A119S was associated with PCa risk under recessive model in overall population (OR = 1.37, 95%CI = 1.04-1.80, P = 0.03). The results suggest that L432V, N453S, and A119S polymorphisms of CYP1B1 might be associated with the susceptibility of PCa. Further larger and well-designed multicenter studies are warranted to validate these findings.
    PLoS ONE 07/2013; 8(7):e68634. DOI:10.1371/journal.pone.0068634 · 3.53 Impact Factor
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    • "CYP3A4*1B has a higher frequency in men from African descent than Caucasian and is absent in Asian men [121] [122] [123] [124] [125], but case-control studies didn't find an association between CYP3A4*1B and PCa risk in men of African descent who had a high frequency of the variant [78] [111] [124] [126]. In addition, reports in Caucasian men were contradictory [111] [124] [127]. Studies for the association between CYP3A4*1B and the progression of PCa were also inconclusive, some studies reported CYP3A4*1B is associated with aggressive PCa in Caucasian and African American men [122] [123] [125] [127] [128], however others studies disagreed [129] [130] [131]. "
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    American Journal of Cancer Research 01/2013; 3(2):127-151. · 3.97 Impact Factor
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    • "Both genes are related to the balance of androgen and estrogen in the prostate gland, which play a significant role for maintaining prostate health (Carruba, 2007, Ellem & Risbridger, 2010). Previous studies have been shown that CYP19A1 (Beuten et al., 2009) and ESR1 (Nicolaiew et al., 2009, McIntyre et al., 2007) may be associated with prostate cancer risk. Furthermore, the SNP-SNP interactions between CYP19A1 and ESR1 genes are observed to be associated with premature ovarian failure (Kim et al., 2011). "
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