Association of variants in estrogen-related pathway genes with prostate cancer risk

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington. .
The Prostate (Impact Factor: 3.57). 01/2013; 73(1). DOI: 10.1002/pros.22534
Source: PubMed


Through mediation of estrogen receptors, estradiol has been shown to have both carcinogenic and anti-carcinogenic effects on the prostate. We performed a population-based case–control study to investigate variants in estrogen-related genes ESR1, ESR2, CYP19A1, CYP1A1, and CYP1B1 and the potential association with risk of prostate cancer (PCa).
We evaluated PCa risk conferred by 73 single nucleotide polymorphisms in 1,304 incident PCa cases and 1,266 age-matched controls. Analysis included stratification by clinical features and assessment of environmental modifiers.
There was evidence of altered risk of developing PCa for variants in ESR1, CYP1A1, and CYP1B1, however, only CYP1B1 rs1056836 retained significance after adjustment for multiple comparisons. An association with risk for more aggressive PCa was observed for variants in ESR1, ESR2, and CYP19A1, but none was significant after adjustment for multiple comparisons. There was no effect modification by obesity.
Germline genetic variation of these estrogen pathway genes may contribute to risk of PCa. Additional studies to validate these results and examine the functional consequence of validated variants are warranted. Prostate 73: 1–10, 2013.

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    • "Several case–control studies were performed to identify the association of CYP1B1 polymorphisms with prostate, bladder and renal cancer risk. However, small sample sizes and limited populations in study design have often yielded inclusive results among the studies [13-29]. The inconsistent conclusions may have resulted from difference ethnic backgrounds and relatively small sample sizes. "
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    ABSTRACT: AbstractBackgroundThe Cytochrome P450 1B1 (CYP1B1) is a key P450 enzyme involved in the metabolism of exogenous and endogenous substrates. Previous studies have reported the existence of CYP1B1 L432V missense polymorphism in prostate, bladder and renal cancers. However, the effects of this polymorphism on the risk of these cancers remain conflicting. Therefore, we performed a meta-analysis to assess the association between L432V polymorphism and the susceptibility of urinary cancers.MethodsWe searched the PubMed database without limits on language for studies exploring the relationship of CYP1B1 L432V polymorphism and urinary cancers. Article search was supplemented by screening the references of retrieved studies manually. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to evaluate the strength of these associations. Simultaneously, publication bias was estimated by funnel plot and Begg’s test with Stata 11 software.ResultsWe observed a significant association between CYP1B1 L432V polymorphism and urinary cancers. The overall OR (95% CI) of CC versus CG was 0.937 (0.881-0.996), the overall OR (95% CI) of CC versus CG + GG was 0.942 (0.890-0.997). Furthermore, we identified reduced risk for CC versus other phenotypes in both prostate and overall urinary cancers, when studies were limited to Caucasian or Asian patients.ConclusionsThis meta-analysis suggests that the CYP1B1 L432V polymorphism is associated with urinary cancer risk.Virtual SlidesThe virtual slide(s) for this article can be found here:
    Diagnostic Pathology 06/2014; 9(1):113. DOI:10.1186/1746-1596-9-113 · 2.60 Impact Factor
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    • "ed 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 · 3.23 Impact Factor
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    ABSTRACT: This review explores the function of estrogen receptors (ERs) and their signaling pathways, and their involvement in the pathogenesis and management of prostate cancer (PCa). We pay special attention to (1) traditional estrogen receptors (ERα and ERβ) and the alternate estrogen receptor, G protein-coupled receptor 30 (GPR30); (2) therapeutic utility of estrogen and antiestrogens; (3) impact of genetic variants of ERs on prostate cancer risk; (4) epigenetic regulation of ERs; (5) downstream signaling of ERs; (6) diagnostic and prognostic value of these receptors; and (7) interaction between ERβ and aryl hydrocarbon receptor or androgen receptor. We also explore (a) the expression patterns of ERs and their spliced isoforms during normal development and the development and progression of PCa; (b) the divergent roles of the estrogen receptors as tumor suppressors and tumor promoters; (c) the possibility of developmental origin of the disease; and (d) the regulation of estrogen receptors via epigenetic modifications such as DNA methylation, histone modification, and microRNA processing. We also review the potential clinical application of various phytoestrogens (genistein, equol, dihydrogenistein, and daidzein), selective estrogen-receptor modulators (SERMs: tamoxifen, toremifene, and raloxifene), pure estrogen antagonists (e.g., fulvestrant), and transdermal estradiol delivered as preventive agents and first-line therapies or combinatory agents. We highlight the need for further studies of the role of ERs in epithelial–mesenchymal transition, prostate stem/progenitor cell function, and cross talk with other nuclear receptors and address the prospect of devising strategies for primordial prevention of PCa through improvements in the understanding of estrogen imprinting in early life.
    Prostate Cancer, 01/2013: pages 383-419; , ISBN: 978-1-4614-6827-1
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