Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa

Incidence of fractures causing hospitalisation in prostate cancer patients: Results from the population-based PCBaSe Sweden

Background: Prostate cancer patients have an increased risk of fractures as a consequence of skeletal metastases and osteoporosis induced by endocrine treatment. Data on incidence of fractures and risks in subgroups of men with prostate cancer are sparse. Our aim with this study is to report the risk of fractures among men with prostate cancer in a nationwide population-based study. Patients and methods: We identified 76,600 Swedish men diagnosed with prostate cancer 1997-2006 in the Prostate Cancer Data Base (PCBaSe) Sweden and compared the occurrence of fractures requiring hospitalisation with the Swedish male population. Results: Only men treated with gonadotropin releasing-hormone (GnRH) agonists or orchiectomy had increased incidence and increased relative risk of fractures requiring hospitalisation. Men treated with GnRH agonists had 9.8 and 6.3/1000 person-years higher incidence of any fracture and hip fracture requiring hospitalisation than the general population. The corresponding increases in incidence for men treated with orchiectomy were 16 and 12/1000 person-years, respectively. Men treated with orchiectomy, GnRH agonists, and antiandrogen monotherapy, had SIR for hip fracture of 2.0 (95% Confidence Interval 1.8-2.2), 1.6 (95% CI 1.5-1.8) and 0.9 (95% CI 0.7-1.1), respectively. Men treated with a curative intent (radical prostatectomy or radiotherapy) or managed with surveillance had no increased risk of fractures. Older men had the highest incidence of fractures while younger men had the highest relative risk. Conclusion: Prostate cancer patients treated with GnRH agonists or orchiectomy have significantly increased risk of fractures requiring hospitalisation while patients treated with antiandrogen monotherapy had no increase in such fractures. In absolute terms the excess risk in men treated with GnRH agonists corresponded to almost 10 extra fractures leading to hospitalisation per 1000 patient-years. Effects on bone density should be considered for men on long-term endocrine treatment. Unwarranted use of orchiectomy and GnRH agonists should be avoided. (C) 2012 Elsevier Ltd. All rights reserved

Serum triglycerides and cancer risk in the metabolic syndrome and cancer (Me-Can) collaborative study

To assess the association between serum triglyceride levels and cancer risk. The metabolic syndrome and cancer project (Me-Can) includes cohorts from Norway, Austria, and Sweden; the current study included data on 257,585 men and 256,512 women. The mean age at study entry was 43.8 years for men and 44.2 years for women. The mean follow-up time was 13.4 years (SD = 8.5) for men and 11.9 years (SD = 7.2) for women. Excluding the first year of follow-up, 23,060 men and 15,686 women were diagnosed with cancer. Cox regression models were used to calculate relative risk (RR) of cancer for triglyceride levels in quintiles and as a continuous variable. RRs were corrected for random error by use of regression dilution ratio. Relative risk for top quintile versus bottom quintile of triglycerides of overall cancer was 1.16 (95% confidence interval 1.06-1.26) in men and 1.15 (1.05-1.27) in women. For specific cancers, significant increases for top quintile versus bottom quintile of triglycerides among men were found for cancers of the colon, respiratory tract, the kidney, melanoma and thyroid and among women, for respiratory, cervical, and non-melanoma skin cancers. Data from our study provided evidence for a possible role of serum triglycerides in cancer development

Plasma selenium concentration and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC)

Background: Some evidence indicates that a low selenium intake may be associated with an increased risk of prostate cancer. Objective: The aim of this study was to investigate the association of plasma selenium concentration with subsequent prostate cancer risk and to examine this association by stage and grade of disease and other factors. Design: A nested case-control study was performed among men in the European Prospective Investigation into Cancer and Nutrition (EPIC). The association between plasma selenium concentration and prostate cancer risk was assessed in 959 men with incident prostate cancer and 1059 matched controls. Results: Overall, plasma selenium concentration was not associated with prostate cancer risk; the multivariate relative risk for men in the highest fifth of selenium concentration compared with the lowest fifth was 0.96 (95% CI: 0.70, 1.31; P for trend = 0.25). There were no significant differences in the association of plasma selenium with risk when analyzed by stage or grade of disease. Similarly, the association of selenium with risk did not differ by smoking status or by plasma alpha- or gamma-tocopherol concentration. Conclusion: Plasma selenium concentration was not associated with prostate cancer risk in this large cohort of European men. Am J Clin Nutr 2008; 88:1567-75

Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study

Background: Previous studies suggest that high plasma concentrations of carotenoids, retinol, or tocopherols may reduce the risk of prostate cancer. Objective: We aimed to examine the associations between plasma concentrations of 7 carotenoids, retinol, a-tocopherol, and,gamma-tocopherol and prostate cancer risk. Design: A total of 137 001 men in 8 European countries participated. After a mean of 6 y, 966 incident cases of prostate cancer with plasma were available. A total of 1064 control subjects were selected and were matched for study center, age, and date of recruitment. The relative risk of prostate cancer was estimated by conditional logistic regression, which was adjusted for smoking status, alcohol intake, body mass index, marital status, physical activity, and education level. Results: Overall, none of the micronutrients examined were significantly associated with prostate cancer risk. For lycopene and the sum of carotenoids, there was evidence of heterogeneity between the associations with risks of localized and advanced disease. These carotenoids were not associated with the risk of localized disease but were inversely associated with the risk of advanced disease. The risk of advanced disease for men in the highest fifth of plasma concentrations compared with men in the lowest fifth was 0.40 (95% CI: 0. 19, 0.88) for lycopene and 0.35 (95% CI: 0. 17, 0.78) for the sum of carotenoids. Conclusions: We observed no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect, an association of dietary choice with delayed detection of prostate cancer, reverse causality, or other factors

Fatty acid composition of plasma phospholipids and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition

Background: Plausible biological mechanisms underlie possible associations between fatty acids in blood and risk of prostate cancer; epidemiologic evidence for an association, however, is inconsistent. Objective: The objectives were to assess the association between plasma phospholipid fatty acids and risk of total prostate cancer by stage and grade. Design: This was a nested case-control analysis of 962 men with a diagnosis of prostate cancer after a median follow-up time of 4.2 y and 1061 matched controls who were taking part in the European Prospective Investigation into Cancer and Nutrition. The fatty acid composition of plasma phospholipids was measured by gas chromatography, and the risk of prostate cancer was estimated by using conditional logistic regression with adjustment for lifestyle variables. Results: We found a positive association between palmitic acid and risk of total, localized, and low-grade prostate cancer. The risk of prostate cancer for men in the highest quintile compared with the lowest quintile of palmitic acid was 1.47 (95% CI: 0.97, 2.23; P for trend = 0.032). We found an inverse association between stearic acid and the risk of total, localized, and low-grade prostate cancer; men in the highest quintile of stearic acid had a relative risk of 0.77 (95% CI: 0.56, 1.06; P for trend = 0.03). There were significant positive associations between myristic, alpha-linolenic, and eicosapentaenoic acids and risk of high-grade prostate cancer. Conclusion: The associations between palmitic, stearic, myristic, alpha-linolenic, and eicosapentaenoic acids and prostate cancer risk may reflect differences in intake or metabolism of these fatty acids between the precancer cases and controls and should be explored further. Am J Clin Nutr 2008; 88: 1353-63

Nitrosamines and Heme Iron and Risk of Prostate Cancer in the European Prospective Investigation into Cancer and Nutrition

Background: The evidence about nitrosamines and heme iron intake and cancer risk is limited, despite the biologic plausibility of the hypothesis that these factors might increase cancer risk. We investigated the association between dietary nitrosamines and heme iron and the risk of prostate cancer among participants of European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: Data on food consumption and complete follow-up for cancer occurrence was available for 139,005 men, recruited in 8 European countries. Estimates of HRs were obtained by proportional hazard models, stratified by age at recruitment, and study center, and adjusted for total energy intake, smoking status, marital status, dairy products, educational level, and body mass index. Results: After a mean follow-up of 10 years, 4,606 participants were diagnosed with first incident prostate cancer. There was no overall association between prostate cancer risk and nitrosamines exposure (preformed and endogenous) or heme iron intake (HR for a doubling of intake: 1.00; 95% CI: 0.98-1.03 for N-Nitrosodimethlyamine, 0.95; 95% CI: 0.88-1.03 for endogenous Nitrosocompounds, and 1.00; 95 CI: 0.97-1.03 for heme iron). Conclusions and Impact: Our findings do not support an effect of nitrosamines (endogenous and exogenous) and heme iron intake on prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 21(3); 547-51. (C) 2012 AACR

Alcohol consumption and the risk for prostate cancer in the European prospective investigation into cancer and nutrition

Alcohol is a risk factor for several types of cancer. However, the results for prostate cancer have been inconsistent, with most studies showing no association. Within the European Prospective Investigation into Cancer and Nutrition, detailed information were collected from 142,607 male participants on the intake of alcoholic beverages at recruitment (for 100% of the cohort) and over lifetime (for 76% of the cohort) between 1992 and 2000. During a median follow-up of 8.7 years, 2,655 prostate cancer cases were observed. Multivariate Cox proportional hazard models were used to examine the association of alcohol consumption at recruitment and average lifetime alcohol consumption with prostate cancer adjusted for age, center, smoking, height, weight, physical activity, and nonalcohol energy intake. Overall, neither alcohol consumption at baseline nor average lifetime alcohol consumption was associated with the risk for prostate cancer in this cohort of men. Men who consumed >= 60 g alcohol per day had a relative risk of 0.88 [95% confidence interval (95% CI) 0.72-1.081 compared with men with an intake of 0.1-4.9 g/d; the respective relative risk for average lifetime intake was 1.09 (95% CI, 0.86-1.39). For advanced prostate cancer (n=537), the relative risks for >= 60 and 0.1-4.9 g alcohol per day at baseline were 0.98 (95% CI, 0.66-1.44) and 1.28 (95% CI, 0.79-2-07), respectively, for average lifetime intake. No statistically significant association was observed for alcohol intake from specific alcoholic beverages. Our results indicate no association between the consumption of alcohol and prostate cancer in this cohort of European men