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BACKGROUND Prostate cancer (PCa) risk-associated single-nucleotide polymorphisms (SNPs) are continuously being discovered. Their ability to identify men at high risk and the impact of increasing numbers of SNPs on predictive performance are not well understood. METHODS Absolute risk for PCa was estimated in a population-based case–control study in Sweden (2,899 cases and 1,722 controls) using family history and three sets of sequentially discovered PCa risk-associated SNPs. Their performance in predicting PCa was assessed by positive predictive values (PPV) and sensitivity. RESULTS SNPs and family history were able to differentiate individual risk for PCa and identify men at higher risk; ∼18% and ∼8% of men in the study had 20-year (55–74 years) absolute risks that were twofold (0.24) or threefold (0.36) greater than the population median risk (0.12), respectively. When predictive performances were compared at absolute risk cutoffs of 0.12, 0.24, or 0.36, PPV increased considerably (∼20%, ∼30%, and ∼37%, respectively) while sensitivity decreased considerably (∼55%, ∼20%, and ∼10%, respectively). In contrast, when increasing numbers of SNPs (5, 11, and 28 SNPs) were used in risk prediction, PPV approached a constant value while sensitivity increased steadily. CONCLUSIONS SNPs discovered to date are suitable for risk prediction while additional SNPs discovered in the future may identify more subjects at higher risk. Men identified as high risk by SNP-based testing may be targeted for PCa screening or chemoprevention. The clinical impact on improving the effectiveness of these interventions can be and should be assessed. Prostate 77:421–430, 2011. © 2010 Wiley-Liss, Inc.

BACKGROUND Genome-wide association studies (GWAS) have led to the discovery of multiple SNPs that are associated with prostate cancer (PCa) risk. These SNPs may potentially be used for risk prediction. To date, there is not a stable estimate of their effect on PCa risk and their contribution to the genetic variation both of which are important for future risk prediction.

Background—Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk. Methods—To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls. Results—After adjusting for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rs1016343: OR=2.07, 95% CI: 1.35-3.20, P=9.4×10 -4 ) and 8q24 Region 1 (rs10090154: OR=2.07, 95% CI: 1.31-3.28, P=0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (ORRegion2=1.92-2.05, P=9.4×10 -4 -0.003, and ORRegion1=1.77-1.81, P=0.01 for all SNPs). Conclusions—Our study shows that multiple prostate cancer risk loci identified in European populations using GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men.

Background—More than a dozen single nucleotide polymorphisms (SNPs) have been associated with prostate cancer (PCa) risk from genome-wide association studies (GWAS). Their association with PCa aggressiveness and clinicopathologic variables is inconclusive. Methods—Twenty PCa risk SNPs implicated in GWAS and fine mapping studies were evaluated in 5,895 PCa cases treated by radical prostatectomy at Johns Hopkins Hospital, where each tumor was uniformly graded and staged using the same protocol. Results—For 18 of the 20 SNPs examined, no statistically significant differences (P > 0.05) were observed in risk allele frequencies between patients with more aggressive (Gleason Scores ≥ 4+3, or stage ≥ T3b, or N+) or less aggressive disease (Gleason Scores ≤ 3+4, and stage ≤ T2, and N0). For the two SNPs that had significant differences between more and less aggressive disease (rs2735839 in KLK3 (P = 8.4 × 10 −7 ) and rs10993994 in MSMB (P = 0.046), the alleles that are associated with increased risk for PCa were more frequent in patients with less aggressive disease. Since these SNPs are known to be associated with PSA levels in men without PCa diagnoses, these latter associations may reflect the enrichment of low grade, low stage cases diagnosed by contemporary disease screening with PSA.

BACKGROUND TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated. METHODS Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2′-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR. RESULTS We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3. CONCLUSION We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development. Prostate 69:327–335, 2009. © 2008 Wiley-Liss, Inc.

BACKGROUND Genome-wide association studies (GWAS) have identified approximately three dozen single nucleotide polymorphisms (SNPs) consistently associated with prostate cancer (PCa) risk. Despite the reproducibility of these associations, the molecular mechanism for most of these SNPs has not been well elaborated as most lie within non-coding regions of the genome. Androgens play a key role in prostate carcinogenesis. Recently, using ChIP-on-chip technology, 22,447 androgen receptor (AR) binding sites have been mapped throughout the genome, greatly expanding the genomic regions potentially involved in androgen-mediated activity. METHODOLOGY/PRINCIPAL FINDINGS To test the hypothesis that sequence variants in AR binding sites are associated with PCa risk, we performed a systematic evaluation among two existing PCa GWAS cohorts; the Johns Hopkins Hospital and the Cancer Genetic Markers of Susceptibility (CGEMS) study population. We demonstrate that regions containing AR binding sites are significantly enriched for PCa risk-associated SNPs, that is, more than expected by chance alone. In addition, compared with the entire genome, these newly observed risk-associated SNPs in these regions are significantly more likely to overlap with established PCa risk-associated SNPs from previous GWAS. These results are consistent with our previous finding from a bioinformatics analysis that one-third of the 33 known PCa risk-associated SNPs discovered by GWAS are located in regions of the genome containing AR binding sites. CONCLUSIONS/SIGNIFICANCE The results to date provide novel statistical evidence suggesting an androgen-mediated mechanism by which some PCa associated SNPs act to influence PCa risk. However, these results are hypothesis generating and ultimately warrant testing through in-depth molecular analyses. Prostate 72:376–385, 2012. © 2011 Wiley Periodicals, Inc.

Genome-wide association studies (GWAS) have led to the discovery of multiple single nucleotide polymorphisms (SNPs) that are associated with prostate cancer (PCa) risk. These SNPs may potentially be used for risk prediction. To date, there is not a stable estimate of their effect on PCa risk and their contribution to the genetic variation both of which are important for future risk prediction.A literature review was conducted to identify SNPs associated with PCa risk with the following criteria: (1) GWAS in the Caucasian population; (2) SNPs with P-value1.0×10(-6); and (3) one SNP from each independent LD block. A meta-analysis was performed to estimate combined odds ratio (OR) and its 95% confidence interval (CI) for the identified SNPs. The proportion of total genetic variance that is attributable by each of these SNPs was also estimated.Thirty PCa risk-associated SNPs were identified. These SNPs had OR estimates between 1.12 and 1.47 except for marker rs16901979 (OR=1.80). Significant heterogeneity in OR estimates was found among different studies for 13 SNPs. The proportion of total genetic variance attributed by each SNP ranged between 0.2% and 0.9%. These 30 SNPs explained ∼13.5% of the total genetic variance of PCa risk in the Caucasian population.This study provides more stable OR estimates for PCa risk-associated SNPs, which is an important baseline for the effect of these SNPs in risk prediction. These SNPs explain a considerable proportion of genetic variance, however, the majority of genetic variance has yet to be explained.

Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk.To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls.After adjustment for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rs1016343: OR = 2.07, 95% CI: 1.35-3.20, P = 9.4 x 10(-4)) and 8q24 Region 1 (rs10090154: OR = 2.07, 95% CI: 1.31-3.28, P = 0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (OR(Region2) = 1.92-2.05, P = 9.4 x 10(-4) to 0.003, and OR(Region1) = 1.77-1.81, P = 0.01 for all SNPs).Our study shows that multiple prostate cancer risk loci identified in European populations by GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men.

TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated.Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2'-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR.We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3.We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development.