Polymorphisms and Prostate Cancer Susceptibility

Androgen Receptor Gene
5-Alpha-Reductase Gene (SRD5A2)
Estrogen Receptor-Beta Gene
E-Cadherin Gene
Toll-like Receptor Genes
Other Genes
Multiple Single Nucleotide Polymorphisms (SNPs) and Genes in Combination
        SNPs identified by genome-wide association studies (GWAS)
        SNPs in candidate genes

 [Note: The advent of large-scale high-throughput genotyping capabilities has resulted in an explosion of association studies between particular genes or genomic regions and prostate cancer risk. It is difficult to assess the import of any individual study. Accordingly, this PDQ Genetics of Prostate Cancer information summary will not attempt to provide an encyclopedic review of all such studies. Rather it will focus on studies that meet one or more of the following criteria: (1) Biological plausibility for the gene that is implicated; (2) Study designed with sufficient power to detect an odds ratio of an appropriate magnitude; (3) Multiple reports demonstrating the same association in the same direction; (4) Similar associations identified in studies of different design; (5) Evidence that the polymorphism is of functional significance; or (6) Existence of a prior hypothesis. However, individual studies may be cited by way of illustrating a specific theoretical point and do not imply that the association is definitive.]

While many research teams have collected multiplex prostate cancer families with the goal of identifying rare, highly penetrant prostate cancer genes, other investigators have studied the potential roles of more common genetic variants as modifiers of prostate cancer risk. While these polymorphisms may not be associated with a large increase in relative risk (RR), these variants may have a high population-attributable risk because they are common. For example, if the population-attributable risk of prostate cancer associated with a genetic variant was 10% among carriers, that would imply that 10% of prostate cancer could be explained by the presence of this variant among carriers. For a rare variant, the proportion of cancer in the population attributed to the variant would be much less than 10%. Thus, a small increase in the RR of prostate cancer associated with a genetic variant that occurs frequently in the general population might, theoretically, account for a larger proportion of all prostate cancers than would the effects of a rare mutation in a gene, such as HPC1. This fact has provided much of the stimulus for studying the role of common genetic variants in the pathogenesis of prostate cancer and other cancers.

Concerns have been raised that differences in ethnic composition (population stratification) may confound the results of some prostate cancer association studies because the incidence of prostate cancer varies according to ethnicity. If a polymorphism also exhibits different frequencies according to race, it may appear to be associated with the disease in the absence of a true causal relationship. This issue was explored in a study in which the CYP3A4-V allele appeared to be statistically associated with increased prostate cancer risk in African Americans (P = .007) and European Americans (P = .02), but not in Nigerians.[1] However, when the investigators added ten markers at other chromosomal regions, the significance for CYP3A4-V in African American men was lost. When the P value above was corrected for the observed population stratification, it was no longer significant. Thus, population admixture and stratification can create false associations (and obscure true associations) between genetic polymorphisms and disease risk.

To minimize confounding by population stratification, family-based association methods can be used. An inverse association has been identified between a single nucleotide polymorphism (SNP) in the CYP17 gene and prostate cancer risk using a set of 461 discordant sibling pairs.[2] Since the siblings are genetically related, population stratification cannot bias this finding. A study of 1,461 Swedish men with prostate cancer in an ethnically homogenous population and 796 control men confirmed an inverse association between a CYP17 variant and prostate cancer risk (P = .04).[3]

In an effort to more comprehensively evaluate the relationship between genetic variants in a particular gene and the risk of a specific cancer, single SNP association studies are augmented by a haplotype -based analytical strategy, in which a series of closely linked SNPs is selected to represent the entire gene. The Multiethnic Cohort Study (MEC) investigators provide a example of this approach as it applies to prostate cancer.[4] Twenty-nine SNPs were used to define four haplotypes spanning the IGF1 gene. The investigators observed modest statistically significant elevations in RR (ranging from 1.19–1.25) for each of the four haplotypes. They concluded that inherited variation in IGF1 may play a role in the risk of prostate cancer.

In addition to the specific examples cited above, there have been additional candidate genes examined for their potential roles in genetic susceptibility to prostate cancer. These include both systematic literature reviews [5-7] and formal meta-analyses evaluating specific candidate genes [8,9] on this complicated and evolving subject. Due to the cross-sectional nature of these studies and the inconsistent results among reports targeting the same gene, these findings currently have no role in clinical decision making. The results of large, adequately powered, prospective analyses of these associations will be required.

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[10] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[11]

Altered activity of the AR due to inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[12,13] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[10,12-22] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1–1.3) and short GGN length (OR, 1.3; 95% CI, 1.1–1.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[23] Subsequently, the large MEC of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[24] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.08–1.69; P = .03).[3]

An analysis of androgen receptor CAG and CGN repeat length polymorphisms targeted African American men from the Flint Men’s Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[25] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[24,26,27] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[28] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[29] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African-American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[30]

Molecular epidemiology studies have also examined genetic polymorphisms of the 5-alpha-reductase type II gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydroxytestosterone (DHT) by 5-alpha-reductase type II.[31] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[32,33]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[34] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[31,35] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[10,31] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[36] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.01–2.08; OR, 1.49; 95% CI, 1.03–2.15).[3] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.09–2.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.14–2.68).[37] A subsequent systematic review and meta-analysis including 27 non-familial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[38]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.35–0.88; OR, 0.57; 95% CI, 0.36–0.90; OR, 0.55; 95% CI, 0.35–0.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.94–2.63).[39] Additional studies are needed to confirm these findings.

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[40] This study awaits replication.

E-cadherin is a tumor suppressor gene in which germline mutations cause a hereditary form of gastric carcinoma. A SNP designated -160→A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene. Because somatic mutations in E-cadherin have been implicated in development of invasive malignancy in a number of different cancers, various investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 26 case-control studies evaluated this genetic variant as a candidate susceptibility allele for seven different cancers.[41] Eight of these studies (~2,600 cases and 2,600 controls) evaluated the risk of prostate cancer. Overall, carriers of the -160→A allele were at 30% increased risk of prostate cancer (95% CI, 1.1–1.6) compared with controls. A second meta-analysis [42] of E-cadherin associations with prostate cancer, reported findings that were quite similar to those noted above,[41] although the overall association between the -160→A allele was not statistically significant (OR, 1.21; 95% CI, 0.97–1.51). The second study was based on a set of individual studies that largely, but not completely, overlapped with those in the earlier report; it was the exclusion of a study judged to have inappropriate controls [42] that accounts for this difference. The overlap in individual studies included in these two meta-analyses is large; therefore, the second meta-analysis does not represent confirmation of the first. Further studies are required to determine whether this finding is reproducible and biologically/clinically important.

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[43] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[44] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[45-49] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[50] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.33–0.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

Molecular epidemiology studies of prostate cancer have also examined associations with vitamin D receptor genes [51-53] and with SNP variants in phase I and phase II metabolism genes such as CYP1A1, CYP2D6, CYP17A2, CYP3A4, GST, NAT1, and NAT2, with inconsistent results.[5] A large meta-analysis studying GSTM1, GSTT1, and GSTP1 found a modest association between prostate cancer susceptibility and GSTM1 (OR, 1.33; 95% CI, 1.15–1.55). This association was seen in whites and Asians but not in blacks.[54] No association with prostate cancer risk was observed for GSTT1 or GSTP1. A smaller case-control study among African American men (208 cases vs. 665 controls) found a modest effect for association to prostate cancer for the GSTP1 105Val allele (OR, 1.56; 95% CI, 0.95–2.58; P = 4.9 × 10^-2). Advanced statistical methods revealed a 2.1-fold increased risk for prostate cancer with combination of GSTP1 and GSTM1 variants. These results need further study and validation.[55]

An association between genetic variants in apoptotic genes and prostate cancer risk has been proposed. The BCL-2 gene has antiapoptotic functions. A case-control study found a 70% decrease in prostate cancer risk in European Americans with the -938AA genotype in the BCL-2 gene and an approximate 60% decrease in risk in Jamaican men of African descent with the 21G allele. Further studies are needed to confirm these findings.[56]

Chronic inflammation has emerged recently as a possible risk factor in the pathogenesis of prostate cancer.[43] A genomic region on chromosome 4q27 has been linked with disease susceptibility in a number of common inflammatory disorders (e.g., celiac disease, systemic lupus erythematosus, and rheumatoid arthritis). A 4q27 candidate locus association study was performed in a population-based study of 825 prostate cancer cases and 734 controls.[57] Seven nucleotide variants across the 4q27 region were selected for analysis, based on highly significant associations in prior studies of autoimmune disease etiology. Overall, there was no significant association between any of the seven variants and risk of prostate cancer. However, analyses stratified by family history of prostate cancer revealed a statistically significant association with SNP rs13119723 in the KIAA1109 region of 4q27 (per-allele OR, 2.37; 95% CI, 1.01–5.57) and prostate cancer risk. This novel finding requires replication in a much larger number of family history–positive prostate cancer patients before its biological significance can be assessed.

A population-based, case-control study from Sweden found a cumulative association of five SNPs representing chromosomal regions 8q24, 17q12, and 17q24.3 to prostate cancer.[58] Cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region. Sixteen SNPs from 8q24, 17q12, and 17q24.3 were analyzed, and due to strong linkage disequilibrium among SNPs in each region, one SNP with the strongest association to prostate cancer was selected to represent each region (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five SNPs had an increasing likelihood of having prostate cancer compared with men carrying none of the five SNPs (P = 6.75 × 10^-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these SNPs had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.93–6.80; P = 1.20 × 10^-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk for prostate cancer (OR, 9.46; 95% CI, 3.62–24.72; P = 1.29 × 10^-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases, 1,157 controls) and Cancer of the Prostate in the Sweden (CAPS) study (2,899 cases, 1,722 controls). The highest risk for prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.64–6.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.83–5.33).[59]

Twenty-three candidate SNPs related to prostate cancer risk in two GWAS studies of European populations were evaluated in a relatively small population of Japanese cases (n = 311) and controls (n = 1,035).[60] Seven of these SNPs (from five genetic loci) were associated with prostate cancer risk (OR, 1.35–1.82). No associations were observed for Gleason score or tumor aggressiveness. Men with six or more risk alleles (27% of cases; 11% of controls) had a sixfold greater prostate cancer risk than those with two or fewer risk alleles (7% of cases; 20% of controls [OR, 6.22; P = 1.5 × 10^-12]). These results confirm the importance of evaluating SNP associations in different ethnic populations and suggest that at least for prostate cancer in the Japanese, combinations of SNPs are sufficiently common in the general population (around 10%) and are associated with a sufficient magnitude of risk that they have some future promise for clinical utility. This latter finding differs from that reported in primarily European populations.[58]

These results support the belief that the genetic basis of prostate cancer is complex, with variants from multiple genetic regions contributing to prostate cancer risk. Because the genes responsible for these associations remain unknown, the biological basis for this complex relationship is unclear. Further, the observations were made in a highly homogenous population, raising concerns regarding the generalizability of the findings. In an era of increasing interest in polygenic risk, this is a conceptually important study, but its applicability to clinical practice is unclear.

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a primarily Caucasian sample.[61] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk for prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic Caucasians, Hispanic Caucasians, and African American men.[62] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic Caucasians (P = .001). In non-Hispanic Caucasians, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < .001). In African Americans, SNPs within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1 showed a significant interaction (P = .014). In non-Hispanic Caucasians, a cumulative risk prostate cancer was observed for men carrying risk alleles at three SNPs in HSD3B2 and CYP19 (OR, 2.20; 95% CI, 1.44–3.38; P = .0003). In Hispanic Caucasians, a cumulative risk for prostate cancer was observed for men carrying risk alleles at two SNPs in CYP19 and CYP24A1 (OR, 4.29; 95% CI, 2.11–8.72; P = .00006). While this study did not evaluate all potentially important SNPs in genes in the steroid hormone pathway, it demonstrates how studies can be performed to evaluate multigenic effects in multiple populations to assess the contribution to prostate cancer risk.

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in Caucasians.[63]

Four SNPs in the p53 pathway (three in genes regulating p53 function including Mdm2, Mdm4, and Hausp and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based Caucasian prostate cancer cohort (N = 4,073).[64] The biologic basis of the various associations identified requires further study, and validation of these findings is needed.

References

1. Kittles RA, Chen W, Panguluri RK, et al.: CYP3A4-V and prostate cancer in African Americans: causal or confounding association because of population stratification? Hum Genet 110 (6): 553-60, 2002.  [PUBMED Abstract]
   
   
2. Douglas JA, Zuhlke KA, Beebe-Dimmer J, et al.: Identifying susceptibility genes for prostate cancer--a family-based association study of polymorphisms in CYP17, CYP19, CYP11A1, and LH-beta. Cancer Epidemiol Biomarkers Prev 14 (8): 2035-9, 2005.  [PUBMED Abstract]
   
   
3. Lindström S, Zheng SL, Wiklund F, et al.: Systematic replication study of reported genetic associations in prostate cancer: Strong support for genetic variation in the androgen pathway. Prostate 66 (16): 1729-43, 2006.  [PUBMED Abstract]
   
   
4. Cheng I, Stram DO, Penney KL, et al.: Common genetic variation in IGF1 and prostate cancer risk in the Multiethnic Cohort. J Natl Cancer Inst 98 (2): 123-34, 2006.  [PUBMED Abstract]
   
   
5. Coughlin SS, Hall IJ: A review of genetic polymorphisms and prostate cancer risk. Ann Epidemiol 12 (3): 182-96, 2002.  [PUBMED Abstract]
   
   
6. Rebbeck TR: Inherited genotype and prostate cancer outcomes. Cancer Epidemiol Biomarkers Prev 11 (10 Pt 1): 945-52, 2002.  [PUBMED Abstract]
   
   
7. Gsur A, Feik E, Madersbacher S: Genetic polymorphisms and prostate cancer risk. World J Urol 21 (6): 414-23, 2004.  [PUBMED Abstract]
   
   
8. Ntais C, Polycarpou A, Ioannidis JP: Vitamin D receptor gene polymorphisms and risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12 (12): 1395-402, 2003.  [PUBMED Abstract]
   
   
9. Ntais C, Polycarpou A, Ioannidis JP: Association of GSTM1, GSTT1, and GSTP1 gene polymorphisms with the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 14 (1): 176-81, 2005.  [PUBMED Abstract]
   
   
10. Ruijter E, van de Kaa C, Miller G, et al.: Molecular genetics and epidemiology of prostate carcinoma. Endocr Rev 20 (1): 22-45, 1999.  [PUBMED Abstract]
    
    
11. Fromont G, Yacoub M, Valeri A, et al.: Differential expression of genes related to androgen and estrogen metabolism in hereditary versus sporadic prostate cancer. Cancer Epidemiol Biomarkers Prev 17 (6): 1505-9, 2008.  [PUBMED Abstract]
    
    
12. Giovannucci E, Stampfer MJ, Krithivas K, et al.: The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 94 (7): 3320-3, 1997.  [PUBMED Abstract]
    
    
13. Stanford JL, Just JJ, Gibbs M, et al.: Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 57 (6): 1194-8, 1997.  [PUBMED Abstract]
    
    
14. Ekman P: Genetic and environmental factors in prostate cancer genesis: identifying high-risk cohorts. Eur Urol 35 (5-6): 362-9, 1999.  [PUBMED Abstract]
    
    
15. Chamberlain NL, Driver ED, Miesfeld RL: The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 22 (15): 3181-6, 1994.  [PUBMED Abstract]
    
    
16. Platz EA, Giovannucci E, Dahl DM, et al.: The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 7 (5): 379-84, 1998.  [PUBMED Abstract]
    
    
17. Bratt O, Borg A, Kristoffersson U, et al.: CAG repeat length in the androgen receptor gene is related to age at diagnosis of prostate cancer and response to endocrine therapy, but not to prostate cancer risk. Br J Cancer 81 (4): 672-6, 1999.  [PUBMED Abstract]
    
    
18. Ekman P, Grönberg H, Matsuyama H, et al.: Links between genetic and environmental factors and prostate cancer risk. Prostate 39 (4): 262-8, 1999.  [PUBMED Abstract]
    
    
19. Lange EM, Chen H, Brierley K, et al.: The polymorphic exon 1 androgen receptor CAG repeat in men with a potential inherited predisposition to prostate cancer. Cancer Epidemiol Biomarkers Prev 9 (4): 439-42, 2000.  [PUBMED Abstract]
    
    
20. Edwards SM, Badzioch MD, Minter R, et al.: Androgen receptor polymorphisms: association with prostate cancer risk, relapse and overall survival. Int J Cancer 84 (5): 458-65, 1999.  [PUBMED Abstract]
    
    
21. Correa-Cerro L, Wöhr G, Häussler J, et al.: (CAG)nCAA and GGN repeats in the human androgen receptor gene are not associated with prostate cancer in a French-German population. Eur J Hum Genet 7 (3): 357-62, 1999.  [PUBMED Abstract]
    
    
22. Mononen N, Ikonen T, Autio V, et al.: Androgen receptor CAG polymorphism and prostate cancer risk. Hum Genet 111 (2): 166-71, 2002.  [PUBMED Abstract]
    
    
23. Zeegers MP, Kiemeney LA, Nieder AM, et al.: How strong is the association between CAG and GGN repeat length polymorphisms in the androgen receptor gene and prostate cancer risk? Cancer Epidemiol Biomarkers Prev 13 (11 Pt 1): 1765-71, 2004.  [PUBMED Abstract]
    
    
24. Freedman ML, Pearce CL, Penney KL, et al.: Systematic evaluation of genetic variation at the androgen receptor locus and risk of prostate cancer in a multiethnic cohort study. Am J Hum Genet 76 (1): 82-90, 2005.  [PUBMED Abstract]
    
    
25. Lange EM, Sarma AV, Ray A, et al.: The androgen receptor CAG and GGN repeat polymorphisms and prostate cancer susceptibility in African-American men: results from the Flint Men's Health Study. J Hum Genet 53 (3): 220-6, 2008.  [PUBMED Abstract]
    
    
26. Panz VR, Joffe BI, Spitz I, et al.: Tandem CAG repeats of the androgen receptor gene and prostate cancer risk in black and white men. Endocrine 15 (2): 213-6, 2001.  [PUBMED Abstract]
    
    
27. Gilligan T, Manola J, Sartor O, et al.: Absence of a correlation of androgen receptor gene CAG repeat length and prostate cancer risk in an African-American population. Clin Prostate Cancer 3 (2): 98-103, 2004.  [PUBMED Abstract]
    
    
28. Mononen N, Syrjäkoski K, Matikainen M, et al.: Two percent of Finnish prostate cancer patients have a germ-line mutation in the hormone-binding domain of the androgen receptor gene. Cancer Res 60 (22): 6479-81, 2000.  [PUBMED Abstract]
    
    
29. Koivisto PA, Hyytinen ER, Matikainen M, et al.: Germline mutation analysis of the androgen receptor gene in Finnish patients with prostate cancer. J Urol 171 (1): 431-3, 2004.  [PUBMED Abstract]
    
    
30. Hu SY, Liu T, Liu ZZ, et al.: Identification of a novel germline missense mutation of the androgen receptor in African American men with familial prostate cancer. Asian J Androl 12 (3): 336-43, 2010.  [PUBMED Abstract]
    
    
31. Reichardt JK, Makridakis N, Henderson BE, et al.: Genetic variability of the human SRD5A2 gene: implications for prostate cancer risk. Cancer Res 55 (18): 3973-5, 1995.  [PUBMED Abstract]
    
    
32. Brawley OW, Ford LG, Thompson I, et al.: 5-Alpha-reductase inhibition and prostate cancer prevention. Cancer Epidemiol Biomarkers Prev 3 (2): 177-82, 1994.  [PUBMED Abstract]
    
    
33. Ross RK, Bernstein L, Lobo RA, et al.: 5-alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339 (8798): 887-9, 1992.  [PUBMED Abstract]
    
    
34. Davis DL, Russell DW: Unusual length polymorphism in human steroid 5 alpha-reductase type 2 gene (SRD5A2). Hum Mol Genet 2 (6): 820, 1993.  [PUBMED Abstract]
    
    
35. Kantoff PW, Febbo PG, Giovannucci E, et al.: A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev 6 (3): 189-92, 1997.  [PUBMED Abstract]
    
    
36. Ntais C, Polycarpou A, Ioannidis JP: SRD5A2 gene polymorphisms and the risk of prostate cancer: a meta-analysis. Cancer Epidemiol Biomarkers Prev 12 (7): 618-24, 2003.  [PUBMED Abstract]
    
    
37. Wang C, Tao W, Chen Q, et al.: SRD5A2 V89L polymorphism and prostate cancer risk: a meta-analysis. Prostate 70 (2): 170-8, 2010.  [PUBMED Abstract]
    
    
38. Li J, Coates RJ, Gwinn M, et al.: Steroid 5-{alpha}-reductase Type 2 (SRD5a2) gene polymorphisms and risk of prostate cancer: a HuGE review. Am J Epidemiol 171 (1): 1-13, 2010.  [PUBMED Abstract]
    
    
39. Sarma AV, Dunn RL, Lange LA, et al.: Genetic polymorphisms in CYP17, CYP3A4, CYP19A1, SRD5A2, IGF-1, and IGFBP-3 and prostate cancer risk in African-American men: the Flint Men's Health Study. Prostate 68 (3): 296-305, 2008.  [PUBMED Abstract]
    
    
40. Thellenberg-Karlsson C, Lindström S, Malmer B, et al.: Estrogen receptor beta polymorphism is associated with prostate cancer risk. Clin Cancer Res 12 (6): 1936-41, 2006.  [PUBMED Abstract]
    
    
41. Wang GY, Lu CQ, Zhang RM, et al.: The E-cadherin gene polymorphism 160C->A and cancer risk: A HuGE review and meta-analysis of 26 case-control studies. Am J Epidemiol 167 (1): 7-14, 2008.  [PUBMED Abstract]
    
    
42. Qiu LX, Li RT, Zhang JB, et al.: The E-cadherin (CDH1)--160 C/A polymorphism and prostate cancer risk: a meta-analysis. Eur J Hum Genet 17 (2): 244-9, 2009.  [PUBMED Abstract]
    
    
43. De Marzo AM, Platz EA, Sutcliffe S, et al.: Inflammation in prostate carcinogenesis. Nat Rev Cancer 7 (4): 256-69, 2007.  [PUBMED Abstract]
    
    
44. Akira S, Takeda K: Toll-like receptor signalling. Nat Rev Immunol 4 (7): 499-511, 2004.  [PUBMED Abstract]
    
    
45. Zheng SL, Augustsson-Bälter K, Chang B, et al.: Sequence variants of toll-like receptor 4 are associated with prostate cancer risk: results from the CAncer Prostate in Sweden Study. Cancer Res 64 (8): 2918-22, 2004.  [PUBMED Abstract]
    
    
46. Chen YC, Giovannucci E, Lazarus R, et al.: Sequence variants of Toll-like receptor 4 and susceptibility to prostate cancer. Cancer Res 65 (24): 11771-8, 2005.  [PUBMED Abstract]
    
    
47. Cheng I, Plummer SJ, Casey G, et al.: Toll-like receptor 4 genetic variation and advanced prostate cancer risk. Cancer Epidemiol Biomarkers Prev 16 (2): 352-5, 2007.  [PUBMED Abstract]
    
    
48. Sun J, Wiklund F, Zheng SL, et al.: Sequence variants in Toll-like receptor gene cluster (TLR6-TLR1-TLR10) and prostate cancer risk. J Natl Cancer Inst 97 (7): 525-32, 2005.  [PUBMED Abstract]
    
    
49. Chen YC, Giovannucci E, Kraft P, et al.: Association between Toll-like receptor gene cluster (TLR6, TLR1, and TLR10) and prostate cancer. Cancer Epidemiol Biomarkers Prev 16 (10): 1982-9, 2007.  [PUBMED Abstract]
    
    
50. Stevens VL, Hsing AW, Talbot JT, et al.: Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk. Int J Cancer 123 (11): 2644-50, 2008.  [PUBMED Abstract]
    
    
51. Taylor JA, Hirvonen A, Watson M, et al.: Association of prostate cancer with vitamin D receptor gene polymorphism. Cancer Res 56 (18): 4108-10, 1996.  [PUBMED Abstract]
    
    
52. Ingles SA, Ross RK, Yu MC, et al.: Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 89 (2): 166-70, 1997.  [PUBMED Abstract]
    
    
53. Cicek MS, Liu X, Schumacher FR, et al.: Vitamin D receptor genotypes/haplotypes and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 15 (12): 2549-52, 2006.  [PUBMED Abstract]
    
    
54. Mo Z, Gao Y, Cao Y, et al.: An updating meta-analysis of the GSTM1, GSTT1, and GSTP1 polymorphisms and prostate cancer: a HuGE review. Prostate 69 (6): 662-88, 2009.  [PUBMED Abstract]
    
    
55. Lavender NA, Benford ML, VanCleave TT, et al.: Examination of polymorphic glutathione S-transferase (GST) genes, tobacco smoking and prostate cancer risk among men of African descent: a case-control study. BMC Cancer 9: 397, 2009.  [PUBMED Abstract]
    
    
56. Kidd LR, Coulibaly A, Templeton TM, et al.: Germline BCL-2 sequence variants and inherited predisposition to prostate cancer. Prostate Cancer Prostatic Dis 9 (3): 284-92, 2006.  [PUBMED Abstract]
    
    
57. Tindall EA, Hoang HN, Southey MC, et al.: The 4q27 locus and prostate cancer risk. BMC Cancer 10: 69, 2010.  [PUBMED Abstract]
    
    
58. Zheng SL, Sun J, Wiklund F, et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 (9): 910-9, 2008.  [PUBMED Abstract]
    
    
59. Xu J, Sun J, Kader AK, et al.: Estimation of absolute risk for prostate cancer using genetic markers and family history. Prostate 69 (14): 1565-72, 2009.  [PUBMED Abstract]
    
    
60. Yamada H, Penney KL, Takahashi H, et al.: Replication of prostate cancer risk loci in a Japanese case-control association study. J Natl Cancer Inst 101 (19): 1330-6, 2009.  [PUBMED Abstract]
    
    
61. Cunningham JM, Hebbring SJ, McDonnell SK, et al.: Evaluation of genetic variations in the androgen and estrogen metabolic pathways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol Biomarkers Prev 16 (5): 969-78, 2007.  [PUBMED Abstract]
    
    
62. Beuten J, Gelfond JA, Franke JL, et al.: Single and multigenic analysis of the association between variants in 12 steroid hormone metabolism genes and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 18 (6): 1869-80, 2009.  [PUBMED Abstract]
    
    
63. Collin SM, Metcalfe C, Zuccolo L, et al.: Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 18 (9): 2528-39, 2009.  [PUBMED Abstract]
    
    
64. Sun T, Lee GS, Oh WK, et al.: Single-nucleotide polymorphisms in p53 pathway and aggressiveness of prostate cancer in a Caucasian population. Clin Cancer Res 16 (21): 5244-51, 2010.  [PUBMED Abstract]