[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, 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 relative risk 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 mutation in a rare 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 in an ethnically homogenous population with prostate cancer compared with 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 recent 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 relative risk (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, as well as 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 gene variants have been examined in relation to both prostate cancer risk and disease progression. The androgen receptor is expressed during all stages of prostate carcinogenesis.[10] Altered activity of the androgen receptor due to inherited variants of the androgen receptor gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the androgen receptor gene (located on the X chromosome) have been associated with the risk of prostate cancer.[11,12] 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.[10-21] 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 1, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[22] 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.[23] A study of 1,461 Swedish men with prostate cancer compared with 796 control men reported an association between androgen receptor (AR) alleles with greater than 22 CAG repeats and prostate cancer (OR = 1.35; 95% CI, 1.08–1.69; P = .03).[3]

The most recent 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.[24] This population-based study of 131 African-American prostate cancer patients and 340 screen-negative African-American controls showed no evidence of an association between shorter androgen receptor (AR) repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[23,25,26] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African-American men.

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.[27] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[28,29]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[30] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[27,31] 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.[10,27] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, though a relationship could not be definitively excluded.[32] 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 compared with 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]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism and degradation of androgens (CYP17, CYP3A4, CYP19A1, andSRD5A2) 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 protective effect (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).[33] 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 23% and a 35% risk for localized disease.[34] This study awaits replication.

Molecular epidemiology studies of prostate cancer have also examined associations with vitamin D receptor genes [35-37] and with SNP variants in phase I and phase II genes such as CYP1A1, CYP2D6, CYP17A2, CYP3A4, GST, and NAT1 and NAT2, with inconsistent results.[5]

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.[38]

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.[39] 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]). Odds ratios (OR) 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 for trend, 6.75x10^-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these SNPs had a significant association to prostate cancer (OR = 4.47; 95% CI, 2.93-6.80; P = 1.20x10^-13). When family history was added in as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger association to prostate cancer (OR = 9.46; 95% CI, 3.62-24.72; P = 1.29x10^-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%. 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.

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-controls studies evaluated this genetic variant as a candidate susceptibility allele for seven different cancers. 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. Further studies are required to determine whether this finding is reproducible.[40]

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