In the analyses presented here, we examined the association between prostate cancer risk and 13 SNPs recently highlighted by two GWAS (1
). Overall, SNPs on chromosomes 6q25, 7p15, 7q21, 8q24, 10q11, 11q13, 17q12, 19q33 and Xp11 were significantly associated with prostate cancer risk in our population-based study.
Of the seven SNPs described by Eeles et al
. (2008), only one, rs2660753 at 3q12, was not significantly associated with prostate cancer risk in our population. This result is consistent with a recent replication study presented by Kote-Jarai and colleagues (2008) that examined data from the PRACTICAL (Pr
ostate cancer a
iation group t
terations in the genome) consortium and includes studies from 13 centers (19
). They observed a weaker association of SNP rs2660753 with prostate cancer risk than previously reported (1
). In stage two of the initial study by Eeles et al
. (2008) a per allele OR of 1.18 (95% CI: 1.06–1.31) was observed (1
), while a reduced OR of 1.08 (95% CI: 1.00–1.16) was noted in the PRACTICAL replication study (19
). This latter result could be driven in part by the study population presented here, which is a part of PRACTICAL and provided the largest number of cases and controls to that consortium effort (19
). Of the seven putatively risk-associated SNPs reported by Thomas and colleagues (2008) (4
), again only one, rs4962416, was not significantly associated with prostate cancer risk in our study. A number of explanations could account for the lack of an association between these SNPs, rs2660753 and rs4962416, in our study. It may be due to different study designs and populations, the reduced sample size of our study compared to the initial GWAS or, alternatively, these differences may be due to chance. Additional studies are needed to determine the significance of the relationship between rs2660753 and rs4962416 and prostate cancer risk.
We then considered whether a first-degree family history of prostate cancer modified the effect of each SNP investigated. Stratification according to family history did not significantly modify the effect of most SNPs, except two. SNP rs2735839 at 19q33.3 is situated amongst a cluster of kallikrein genes, including KLK3
that encodes prostate-specific antigen (PSA) (26
). The minor allele is associated with a significantly reduced risk of prostate cancer in men without a family history, while no association was seen in men with a family history of disease. However, this result could be due to chance, given the limited number of cases and controls with a family history. There is currently debate as to whether the association previously reported between this polymorphism and prostate cancer risk is confounded by PSA screening. The association with rs2735839 was first observed in a GWAS where controls had a baseline PSA of <0.5ng/mL (1
). In the concurrent CGEMS GWAS, an association between this SNP and prostate cancer risk was not identified (4
), and when rs2735839 was examined among controls only, a strong correlation was found with PSA levels (27
). In our study we found a significant association between prostate cancer risk and rs2735839 and we also found a significant association between PSA level and rs2735839 genotype (p=0.0085), where the minor allele was associated with a decrease in mean PSA levels in controls. As PSA screening was prevalent in men in our study (73% of men with a family history and 58% of men without a family history reported having a PSA test within the past five years), it may be that the decrease in risk associated with rs2735839 is due to confounding. Adjusting for prostate cancer screening history did not significantly change our risk estimate, but the adjusted confidence interval includes the null. In addition, the association between rs2735839 and prostate cancer risk has been replicated in other populations where PSA screening is virtually absent (19
). It is clear that the relationship between this SNP and prostate cancer risk needs to be investigated in additional datasets before we can determine whether there is a true association with risk of disease.
The effect of rs4242382 at 8q24 was also modified by family history. The minor allele was associated with a significant increase in risk in men without a family history of prostate cancer but not in those with a family history of the disease. This result appears to reflect the somewhat higher MAF in controls with a family history than in controls without a family history of prostate cancer. As the control group is population-based and family history wasn’t a determining factor for inclusion, this may reflect a true difference in the effect of this SNP on prostate cancer risk according to family history of the disease. However, the result may also be due to the limited number of cases and controls with a family history of prostate cancer in this population. The results from this analysis are in contrast to a previous study by Wang and colleagues (2007) (17
). That study examined SNP rs1447295, which is in complete linkage disequilibrium (r2
=1) with rs4242382, and found a stronger association between rs1447295 SNP genotype and risk in familial prostate cancer cases compared to controls than that observed between sporadic prostate cancer cases versus controls. It has to be noted that for both of the associations described above, the analyses are underpowered due to the limited number of cases and controls with a family history of prostate cancer.
Currently clinicians are unable to distinguish between those patients with more aggressive forms of prostate cancer that may lead to adverse outcomes and those whose disease will follow a more indolent course. There is a need for markers that can identify men who may benefit most from aggressive treatment regimens or early phase clinical trials. deCODE genetics currently offers an eight marker deCODE ProCa™ genetic risk profile for Caucasian males of European ancestry, however it is not a determinative diagnostic test nor do the SNP genotypes correlate with more aggressive prostate cancer features (www.decodediagnostics.com
). Zheng and colleagues (2008) have also proposed a five SNP genetic test panel that purports to identify men with an increased risk of disease (28
). The relative risk estimate is 4.47 (95% CI 2.93–6.80) for the small proportion of men having four of the five at-risk alleles. However, this test provides no greater predictive value than having a strong family history defined by having two or more affected first degree relatives (OR 4.9: 95% CI 2.0–12.3 (29
); OR 5.08: 95% CI 3.31–7.79 (25
)). In addition, a recent analysis (30
) has shown that these five SNPs do not improve prediction models for risk of developing prostate cancer or of disease-specific mortality in Caucasian men once currently known risk predictors (age, serum PSA and family history) and outcome predictors (age, diagnostic PSA, Gleason score, stage, primary treatment), respectively, are taken into account.
None of the SNPs examined in our case-control study were associated with a composite measure of disease aggressiveness or tumor stage. However, the effects of rs10993994 and rs5945619 on prostate cancer risk were significantly different by Gleason score. SNP rs10993994, at 10q11, was associated with a significantly increased risk of disease in men with lower Gleason scores but not in men with higher Gleason scores. This SNP lies two base pairs upstream of the transcription start site of MSMB
, a gene encoding prostatic secretory protein of 94 amino acids (PSP94), which is secreted into both seminal fluid and blood (31
). PSP94 is a tumor suppressor protein that may impede prostate cancer growth through the promotion of apoptosis (32
), inhibition of the secretion of a matrix metalloproteinase that is implicated in tumor metastasis (31
), and by decreasing tumor-associated, VEGF-mediated vascularization (34
). Given the function of this protein, it is not clear why there is an association limited to cases with a lower rather than a higher Gleason score; this result may be due to the smaller number of cases in the higher Gleason score group or another gene(s) in this region, and not MSMB
, may be contributing to the deleterious effect.
The effect of rs5945619 at Xp11 on prostate cancer risk was also modified by Gleason score, as there was a significant increase in risk of disease in cases with a higher compared to lower Gleason score (interaction p=0.03). SNP rs5945619 lies in a two Mb LD block between the NUDT10
genes. While little is known about these particular genes, they belong to a subgroup of proteins that have been functionally linked to vesicle trafficking, stress responses, DNA repair, and apoptosis (35
). Although the test for homogeneity between cases with lower versus higher Gleason scores is only nominally significant, the potential role that these genes play in tumor development, and the direction of the association, suggests that this finding warrants replication in a larger data set. While not statistically significant, the relative risk of prostate cancer was also greater in men with a higher Gleason score than in those with comparatively lower scores in the replication study of Kote-Jarai and colleagues (2008) (19
The results presented here confirm the importance of a number of recently highlighted loci in prostate cancer susceptibility, even though the variant alleles of these SNPs only confer a low to moderate association with risk of the disease. The effects of most of these polymorphisms do not appear to be modified by a family history of prostate cancer, except for rs4242382 at 8q24 and rs2735839 at 19q33. Two SNPs, rs10993994 at 10q11 and rs5945619 at Xp11, were associated with Gleason score, while the remaining SNPs were not associated with indicators of disease aggressiveness or tumor stage. One shortcoming of this study was the limited power due to the smaller numbers in the stratified sub-groups. Because of this, it is important that these results be replicated in larger population-based studies. In conclusion, while there has recently been success in identifying prostate cancer susceptibility loci, future studies should also focus on identifying genetic variants that predict risk of more aggressive disease and thereby may predict which patients are at higher risk for subsequent metastasis and disease-specific mortality.
Statement of Translational Relevance
Currently clinicians are unable to clearly distinguish between men with less aggressive as compared to more aggressive forms of prostate cancer. Finding genetic variants that identify men with aggressive disease, who have a higher risk for prostate cancer-specific mortality, may help clinicians make more informed treatment recommendations. Recent genome-wide association studies have identified a number of single nucleotide polymorphisms (SNPs) associated with prostate cancer risk, but it is unclear whether these particular SNPs uniquely identify the subset of men at higher risk based on clinical features of disease or further enhance risk in men with a family history of prostate cancer. The work presented here addresses these issues and we hope that it will encourage future studies aimed at identifying genetic variants that may distinguish high-risk subsets of men suitable for novel therapeutic trials.