Evaluation of Genetic Variations in the Androgen and Estrogen Metabolic Pathways as Risk Factors for Sporadic and Familial Prostate Cancer

Abstract

Previous studies suggest that enzymes involved in the androgen metabolic pathway are susceptibility factors for prostate cancer. Estrogen metabolites functioning as genotoxins have also been proposed as risk factors. In this study, we systematically tested the hypothesis that common genetic variations for those enzymes involved in the androgen and estrogen metabolic pathways increase risk for sporadic and familial prostate cancer. From these two pathways, 46 polymorphisms (34 single nucleotide polymorphisms, 10 short tandem repeat polymorphisms, and 2 null alleles) in 25 genes were tested for possible associations. Those genes tested included PRL, LHB, CYP11A1, HSD3B1, HSD3B2, HSD17B2, CYP17, SRD5A2, AKR1C3, UGT2B15, AR, SHBG, and KLK3 from the androgen pathway and CYP19, HSD17B1, CYP1A1, CYP1A2, CYP1B1, COMT, GSTP1, GSTT1, GSTM1, NQO1, ESR1, and ESR2 from the estrogen pathway. A case-control study design was used with two sets of cases: familial cases with a strong prostate cancer family history (n = 438 from 178 families) and sporadic cases with a negative prostate cancer family history (n = 499). The controls (n = 493) were derived from a population-based collection. Our results provide suggestive findings for an association with either familial or sporadic prostate cancer with polymorphisms in four genes: AKR1C3, HSD17B1, NQO1, and GSTT1. Additional suggestive findings for an association with clinical variables (disease stage, grade, and/or node status) were observed for single nucleotide polymorphisms in eight genes: HSD3B2, SRD5A2, SHBG, ESR1, CYP1A1, CYP1B1, GSTT1, and NQO1. However, none of the findings were statistically significant after appropriate corrections for multiple comparisons. Given that the point estimates for the odds ratio for each of these polymorphisms are <2.0, much larger sample sizes will be required for confirmation. (Cancer Epidemiol Biomarkers Prev 2007;16(5):969 -78)

Estrogen receptor β and the progression of prostate cancer: role of 5α-androstane-3β,17β-diol

“…Therefore, at least in the early stages of PC, 3b-Adiol formation may shift the equilibrium versus a slowing down of progression and invasiveness of the tumor cells. This exciting hypothesis has strong support in clinical observations, demonstrating that genetic alteration of several enzymes involved in androgenic steroid metabolism is linked to hereditary and sporadic PC susceptibility (Chang et al 2002, Steckelbroeck et al 2004, Bauman et al 2006, Cunningham et al 2007, Neslund-Dudas et al 2007, Park et al 2007, Ross et al 2008, Beuten et al 2009, Mindnich & Penning 2009). It has been established that enzyme responsible for 3b-Adiol formation from the DHT in prostate is AKR1C1; in fact, AKR1C1:AKR1C2 (responsible for 3a-diol formation from the DHT) transcript ratio fells in PC; thus, the data here presented provide clear explanations of these observations, since the reduction of 3b-Adiol levels in favor of 3a-Adiol may be a risk factor for PC in these patients, because the 3b-Adiol 'protective' effect will obviously disappear.…”

Association of Uridine Diphosphate-Glucuronosyltransferase 2B Gene Variants with Serum Glucuronide Levels and Prostate Cancer Risk

“…However, the expression of all three genes has been measured in prostate cancer cell lines (Valentini et al, 2007). The association of the UGT2B15 D85Y polymorphism with prostate cancer has been examined with conflicting results (MacLeod et al, 2000;Gsur et al, 2002;Hajdinjak and Zagradisnik, 2004;Park et al, 2004;Cunningham et al, 2007). Similarly, numerous studies have explored the association of the UGT2B17 CNV and prostate cancer also with inconsistent conclusions (Park et al, 2006(Park et al, , 2007Gallagher et al, 2007;Karypidis et al, 2007;Olsson et al, 2008;Setlur et al, 2010).…”

Variants on ESR1 and their Association with Prostate Cancer Risk: A Meta-analysis

“…rs9340799 and the susceptibility of prostate cancer From the database search, we have identified ten studies that have reported the association of the variant of rs9340799 (XbaI, IVS1-351) and prostate cancer (Modugno et al, 2001;Suzuki et al, 2003;Fukatsu et al, 2004;Hernandez et al, 2006;Cunningham et al, 2007;Beuten et al, 2009;Gupta et al, 2010;Sissung et al, 2011;Szendroi et al, 2011;Safarinejad et al, 2012); however, one study reported by Hernandez et al (2006) had the same study population with the other study reported by Beuten et al (2009) and the it was excluded from our further study. In total, nine studies that have recruited a total of 2,792 prostate cancer patients and 3,397 controls with eleven individual study groups were included in the meta-analysis study (Table 1).…”

“…These results indicated that rs9340799 may be a risk factor for prostate cancer and it may acts as a dominant model. rs2234693 and the susceptibility of prostate cancer In total, 17 individual studies were identified in the literature search stage that have evaluated the association between the rs2234693 and prostate cancer (Modugno et al, 2001;Suzuki et al, 2003;Tanaka et al, 2003;Fukatsu et al, 2004;Hernandez et al, 2006;Low et al, 2006;Berndt et al, 2007;Cunningham et al, 2007;Kjaergaard et al, 2007;Onsory et al, 2008;Sobti et al, 2008;Beuten et al, 2009;Gupta et al, 2010;Sonoda et al, 2010;Sissung et al, 2011;Szendroi et al, 2011;Safarinejad et al, 2012). Two of them were excluded for overlapping studied populations (Hernandez et al, 2006;Sobti et al, 2008).…”

“…If an article consisted of more than one population study group then each subgroup was recognized as an individual subgroup study except for one study reported by Cunningham et al(S-Cunningham et al, 2007), which contain a common control group for the familial and sporadic prostate cancer patients and the allele frequency were put together in the cases before the final analysis. …”