Claudia A. Salinas

Multiple Novel Prostate Cancer Predisposition Loci Confirmed by an International Study: The PRACTICAL Consortium

A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10−17). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction. (Cancer Epidemiol Biomarkers Prev 2008;17(8):2052–61)

Clinical Utility of Five Genetic Variants for Predicting Prostate Cancer Risk and Mortality

A recent report suggests that the combination of five single‐nucleotide polymorphisms (SNPs) at 8q24, 17q12, 17q24.3 and a family history of the disease may predict risk of prostate cancer. The present study tests the performance of these factors in prediction models for prostate cancer risk and prostate cancer‐specific mortality.

Use of Aspirin and Other Nonsteroidal Antiinflammatory Medications in Relation to Prostate Cancer Risk

Recent interest has focused on the role that inflammation may play in the development of prostate cancer and whether use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) affects risk. In a population-based case-control study designed to investigate the relation between these medications and prostate cancer risk, detailed exposure data were analyzed from 1,001 cases diagnosed with prostate cancer between January 1, 2002, and December 31, 2005, and 942 age-matched controls from King County, Washington. A significant 21% reduction in the risk of prostate cancer was observed among current users of aspirin compared with nonusers (95% confidence interval (CI): 0.65, 0.96). Long-term use of aspirin (>5 years: odds ratio = 0.76, 95% CI: 0.61, 0.96) and daily use of low-dose aspirin (odds ratio = 0.71, 95% CI: 0.56, 0.90) were also associated with decreased risk. There was no evidence that the association with aspirin use varied by disease aggressiveness, but there was effect modification (P(interaction) = 0.02) with a genetic variant in prostaglandin-endoperoxide synthase 2 (PTGS2) (rs12042763). Prostate cancer risk was not related to use of either nonaspirin NSAIDs or acetaminophen. These results contribute further evidence that aspirin may have chemopreventive activity against prostate cancer and highlight the need for additional research.

Analysis of Recently Identified Prostate Cancer Susceptibility Loci in a Population-based Study: Associations with Family History and Clinical Features

Purpose: Two recent genome-wide association studies have highlighted several single nucleotide polymorphisms (SNPs) purported to be associated with prostate cancer risk. We investigated the significance of these SNPs in a population-based study of Caucasian men, testing the effects of each SNP in relation to family history of prostate cancer and the clinicopathologic features of the disease. Experimental Design: We genotyped 13 SNPs in 1,308 prostate cancer patients and 1,267 unaffected controls frequency matched to cases by five-year age groups. The association of each SNP with disease risk stratified by family history of prostate cancer and clinicopathologic features of the disease was calculated with the use of logistic and polytomous regression. Results: These results confirm the importance of multiple, previously reported SNPs in relation to prostate cancer susceptibility; 11 of the 13 SNPs were significantly associated with risk of developing prostate cancer. However, none of the SNP associations were of comparable magnitude with that associated with having a first-degree family history of the disease. Risk estimates associated with SNPs rs4242382 and rs2735839 varied by family history, whereas risk estimates for rs10993994 and rs5945619 varied by Gleason score. Conclusions: Our results confirm that several recently identified SNPs are associated with prostate cancer risk; however, the variant alleles only confer a low to moderate relative risk of disease and are generally not associated with more aggressive disease features.

Multiple independent genetic variants in the 8q24 region are associated with prostate cancer risk.

Recently, the 8q24 region has been identified as a prostate cancer susceptibility locus in a genome-wide scan of prostate cancer families in Iceland and an admixture scan of African Americans. Further investigations of variants at 8q24 have shown the existence of additional single nucleotide polymorphisms (SNPs) that enhance prostate cancer risk, suggesting the possibility of multiple regions harboring variants for the disease. In the present population-based study of Caucasians (1,308 cases and 1,266 controls) and African Americans (149 cases and 85 controls), we tested the association between prostate cancer and 23 SNPs in the 8q24 region. Fourteen SNPs in Caucasians and 5 SNPs in African Americans were significantly associated with risk of prostate cancer after adjusting for multiple comparisons; of these, 5 SNPs in Caucasians and 3 in African Americans were independently associated with risk. The strongest association was for rs6983561 (carriers of any C allele) with an odds ratio of 1.6 (95% confidence interval, 1.1-2.1) in Caucasians; variants in rs979200, rs1016343, rs7837328, and rs10090154 were also independently associated with risk. In African Americans, the strongest association was for rs7000448 (carriers of any T allele) with an odds ratio of 3.4 (95% confidence interval, 1.3-8.7). In addition, two SNPs that extend the boundaries of the 8q24 region were significantly associated with risk: rs979200 at the centromeric boundary and rs3891248, located in the first intron of the c-MYC gene (IVS1-355), which identifies a new telomeric boundary. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1203–13)

Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk

Background: Chronic inflammation is an important mechanism for the development and progression of prostate cancer (PC). To better understand the potential relationship between genes in the inflammation pathway and PC risk, we evaluated variants in 16 candidate genes. Methods: A total of 143 tagging and amino acid altering single nucleotide polymorphisms (SNPs) were genotyped in Caucasian and African American men participating in one of two population-based, case–control studies (n = 1,458 cases and 1,351 controls). The relative risk of PC was estimated using logistic and polytomous regression models. Results: Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen with rs11574783 in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01–0.63). Cumulatively, four SNPs in genes interleukin 4 (IL4), IL6ST, PTGS2, and signal transducer and activator of transcription 3 (STAT3) conferred a three-fold elevation in PC risk among men carrying the maximum number of high-risk alleles (OR = 2.97, 95% CI: 1.41–6.25, Ptrend = 0.0003). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (Phomogeneity < 0.05), with SNPs in AKT1, PIK3R1, and STAT3 independently associated with more aggressive PC; OR = 5.1 (95% CI: 2.29–11.40, Ptrend = 3.8 × 10−5) for carriers of all high-risk genotypes. Conclusions: These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, however, further studies are needed to replicate our findings. Impact: These results underline the potential importance of the inflammation pathway in PC development and progression. Cancer Epidemiol Biomarkers Prev; 20(5); 923–33. ©2011 AACR.

Vasectomy and the Risk of Prostate Cancer

PURPOSE While the weight of evidence shows no association overall between vasectomy and prostate cancer, there has been some suggestion that an association may exist in subgroups, such as men who have a family history of prostate cancer, men who undergo vasectomy at a younger age or when several decades have passed since the procedure. Studies of risk with long latency periods have been hampered by small sample sizes in subgroups since vasectomy only became widely used in the 1960s and generally prostate cancer has a long latency period. MATERIALS AND METHODS We analyzed data from a recent population based case-control study that was designed specifically to address this issue of risk in subgroups. Interviews were completed with 1,001 men diagnosed with prostate cancer from January 1, 2002 through December 31, 2005 in the Seattle-Puget Sound region and in 942 matched control men. Subjects were black and white men between the ages of 35 and 74 years. Data were analyzed using unconditional logistic regression to calculate the OR as an estimate of the relative risk of prostate cancer associated with various vasectomy parameters. RESULTS The prevalence of vasectomy was similar in cases and controls (36.2% and 36.1%, respectively, adjusted OR 1.0, 95% CI 0.8-1.2). There were also no associations between prostate cancer and age at vasectomy, years elapsed since vasectomy or calendar year of vasectomy. CONCLUSIONS These findings indicate that there is no association between vasectomy and the risk of prostate cancer.