Personalized dietary management of advanced prostate cancer using nutrigenomics: a case report.

While there are emerging reports in the scientific literature on potential associations between cholesterol/lipids and prostate cancer, information on the dietary management of these cancer patients is currently lacking. We report on a 57-year-old white Australian male diagnosed with advanced prostate cancer who had personalized dietary management in preparation for and following his medical treatment: radiation and radical prostatectomy. Dietary recommendations were based on his blood results and nutrigenomic tests which showed a history of and genetic predisposition to dyslipidemia. Nutritional analysis also confirmed the need for dietary modification of his fat intake. Eighteen months post medical and dietary intervention his PSA level was reported at 0.1 ug/L and all blood lipid levels were within reference ranges. At two years there was no detectable disease recurrence and androgen deprivation therapy (ADT) was not required. Personalized dietary recommendations could be a clinically beneficial addition to the multidisciplinary management of prostate cancer patients.

Dietary B group vitamin intake and the bladder cancer risk: a pooled analysis of prospective cohort studies.

PURPOSE: Diet may play an essential role in the aetiology of bladder cancer (BC). The B group complex vitamins involve diverse biological functions that could be influential in cancer prevention. The aim of the present study was to investigate the association between various components of the B group vitamin complex and BC risk. METHODS: Dietary data were pooled from four cohort studies. Food item intake was converted to daily intakes of B group vitamins and pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using Cox-regression models. Dose-response relationships were examined using a nonparametric test for trend. RESULTS: In total, 2915 BC cases and 530,012 non-cases were included in the analyses. The present study showed an increased BC risk for moderate intake of vitamin B1 (HRB1: 1.13, 95% CI: 1.00-1.20). In men, moderate intake of the vitamins B1, B2, energy-related vitamins and high intake of vitamin B1 were associated with an increased BC risk (HR (95% CI): 1.13 (1.02-1.26), 1.14 (1.02-1.26), 1.13 (1.02-1.26; 1.13 (1.02-1.26), respectively). In women, high intake of all vitamins and vitamin combinations, except for the entire complex, showed an inverse association (HR (95% CI): 0.80 (0.67-0.97), 0.83 (0.70-1.00); 0.77 (0.63-0.93), 0.73 (0.61-0.88), 0.82 (0.68-0.99), 0.79 (0.66-0.95), 0.80 (0.66-0.96), 0.74 (0.62-0.89), 0.76 (0.63-0.92), respectively). Dose-response analyses showed an increased BC risk for higher intake of vitamin B1 and B12. CONCLUSION: Our findings highlight the importance of future research on the food sources of B group vitamins in the context of the overall and sex-stratified diet.

Dietary fats and their sources in association with the risk of bladder cancer: A pooled analysis of 11 prospective cohort studies.

The effects of fat intake from different dietary sources on bladder cancer (BC) risk remains unidentified. Therefore, the present study aimed to investigate the association between fat intakes and BC risk by merging world data on this topic. Data from 11 cohort studies in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided sufficient information on fat intake for a total of 2731 BC cases and 544 452 noncases, which yielded 5 400 168 person-years of follow-up. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox-regression models stratified on cohort. Analyses were adjusted for total energy intake in kilocalories, gender, smoking status (model-1) and additionally for sugar and sugar products, beers, wine, dressing and plant-based and fruits intakes (model-2). Among women, an inverse association was observed between mono-unsaturated fatty acids (MUFAs) and BC risk (HR comparing the highest with the lowest tertile: 0.73, 95% CI: 0.58-0.93, P-trend = .01). Overall, this preventative effect of MUFAs on BC risk was only observed for the nonmuscle invasive bladder cancer (NMIBC) subtype (HR: 0.69, 95% CI: 0.53-0.91, P-trend = .004). Among men, a higher intake of total cholesterol was associated with an increased BC risk (HR: 1.37, 95% CI: 1.16-1.61, P-trend = .01). No other significant associations were observed. This large prospective study adds new insights into the role of fat and oils in BC carcinogenesis, showing an inverse association between consumption of MUFAs and the development of BC among women and a direct association between higher intakes of dietary cholesterol and BC risk among men.

Smoking Methylation Marks for Prediction of Urothelial Cancer Risk.

BACKGROUND: Self-reported information may not accurately capture smoking exposure. We aimed to evaluate whether smoking-associated DNA methylation markers improve urothelial cell carcinoma (UCC) risk prediction. METHODS: Conditional logistic regression was used to assess associations between blood-based methylation and UCC risk using two matched case-control samples: 404 pairs from the Melbourne Collaborative Cohort Study (MCCS) and 440 pairs from the Women's Health Initiative (WHI) cohort. Results were pooled using fixed-effects meta-analysis. We developed methylation-based predictors of UCC and evaluated their prediction accuracy on two replication data sets using the area under the curve (AUC). RESULTS: The meta-analysis identified associations (P < 4.7 × 10-5) for 29 of 1,061 smoking-associated methylation sites, but these were substantially attenuated after adjustment for self-reported smoking. Nominally significant associations (P < 0.05) were found for 387 (36%) and 86 (8%) of smoking-associated markers without/with adjustment for self-reported smoking, respectively, with same direction of association as with smoking for 387 (100%) and 79 (92%) markers. A Lasso-based predictor was associated with UCC risk in one replication data set in MCCS [N = 134; odds ratio per SD (OR) = 1.37; 95% CI, 1.00-1.90] after confounder adjustment; AUC = 0.66, compared with AUC = 0.64 without methylation information. Limited evidence of replication was found in the second testing data set in WHI (N = 440; OR = 1.09; 95% CI, 0.91-1.30). CONCLUSIONS: Combination of smoking-associated methylation marks may provide some improvement to UCC risk prediction. Our findings need further evaluation using larger data sets. IMPACT: DNA methylation may be associated with UCC risk beyond traditional smoking assessment and could contribute to some improvements in stratification of UCC risk in the general population.

The association between meat and fish consumption and bladder cancer risk: a pooled analysis of 11 cohort studies.

Evidence on the effects of meat consumption from different sources on the risk of bladder cancer (BC) is limited and controversial. Therefore, this study aimed to evaluate the associations between meat consumption and BC risk using a pooled data approach. Individual data from 11 prospective cohorts comprising 2848 BC cases and 515,697 non-cases with a total of 5,498,025 person-years of follow-up was pooled and analysed to investigate the potential associations between total red meat and products, red meat, processed meat, poultry and total fish and BC risk. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox regression models stratified on cohort. Overall, an increased BC risk was found for high intake of organ meat (HR comparing highest with lowest tertile: 1.18, 95% CI: 1.03, 1.36, p-trend = 0.03). On the contrary, a marginally inverse association was observed for total fish intake and BC risk among men (HR comparing highest with lowest tertile: 0.79, 95% CI 0.65, 0.97, p-trend = 0.04). No associations were observed for other meat sources. Results of this prospective study suggest that organ meat consumption may be associated with BC development. Replication in large-scale prospective studies and investigation of possible causal mechanisms is needed.

Vegetable intake and the risk of bladder cancer in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

BACKGROUND: Although a potential inverse association between vegetable intake and bladder cancer risk has been reported, epidemiological evidence is inconsistent. This research aimed to elucidate the association between vegetable intake and bladder cancer risk by conducting a pooled analysis of data from prospective cohort studies. METHODS: Vegetable intake in relation to bladder cancer risk was examined by pooling individual-level data from 13 cohort studies, comprising 3203 cases among a total of 555,685 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were estimated using Cox proportional hazards regression models stratified by cohort for intakes of total vegetable, vegetable subtypes (i.e. non-starchy, starchy, green leafy and cruciferous vegetables) and individual vegetable types. In addition, a diet diversity score was used to assess the association of the varied types of vegetable intake on bladder cancer risk. RESULTS: The association between vegetable intake and bladder cancer risk differed by sex (P-interaction = 0.011) and smoking status (P-interaction = 0.038); therefore, analyses were stratified by sex and smoking status. With adjustment of age, sex, smoking, energy intake, ethnicity and other potential dietary factors, we found that higher intake of total and non-starchy vegetables were inversely associated with the risk of bladder cancer among women (comparing the highest with lowest intake tertile: HR = 0.79, 95% CI = 0.64-0.98, P = 0.037 for trend, HR per 1 SD increment = 0.89, 95% CI = 0.81-0.99; HR = 0.78, 95% CI = 0.63-0.97, P = 0.034 for trend, HR per 1 SD increment = 0.88, 95% CI = 0.79-0.98, respectively). However, no evidence of association was observed among men, and the intake of vegetable was not found to be associated with bladder cancer when stratified by smoking status. Moreover, we found no evidence of association for diet diversity with bladder cancer risk. CONCLUSION: Higher intakes of total and non-starchy vegetable are associated with reduced risk of bladder cancer for women. Further studies are needed to clarify whether these results reflect causal processes and potential underlying mechanisms.

DNA Methylation in Peripheral Blood and Risk of Gastric Cancer: A Prospective Nested Case-control Study.

DNA methylation in peripheral blood is a potential biomarker of gastric cancer risk which could be used for early detection. We conducted a prospective case-control study nested within the Melbourne Collaborative Cohort Study. Genomic DNA was prepared from blood samples collected a median of 12 years before diagnosis for cases (N = 168). Controls (N = 163) were matched to cases on sex, year of birth, country of birth, and blood sample type using incidence density sampling. Genome-wide DNA methylation was measured using the Infinium HumanMethylation450K Beadchip. Global measures of DNA methylation were defined as the median methylation M value, calculated for each of 13 CpG subsets representing genomic function, mean methylation and location, and reliability of measurement. Conditional logistic regression was conducted to assess associations between these global measures of methylation and gastric cancer risk, adjusting for Helicobacter pylori and other potential confounders. We tested nonlinear associations using quintiles of the global measure distribution. A genome-wide association study of DNA methylation and gastric cancer risk was also conducted (N = 484,989 CpGs) using conditional logistic regression, adjusting for potential confounders. Differentially methylated regions (DMR) were investigated using the R package DMRcate We found no evidence of associations with gastric cancer risk for individual CpGs or DMRs (P > 7.6 × 10-6). No evidence of association was observed with global measures of methylation (OR 1.07 per SD of overall median methylation; 95% confidence interval, 0.80-1.44; P = 0.65). We found no evidence that blood DNA methylation is prospectively associated with gastric cancer risk.Prevention Relevance: We studied DNA methylation in blood to try and predict who was at risk of gastric cancer before symptoms developed, by which stage survival is poor. We did not find any such markers, but the importance of early diagnosis in gastric cancer remains, and the search for markers continues.

Grain and dietary fiber intake and bladder cancer risk: a pooled analysis of prospective cohort studies.

BACKGROUND: Higher intakes of whole grains and dietary fiber have been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for cancer. OBJECTIVES: Because the evidence of association with bladder cancer (BC) is limited, we aimed to assess associations with BC risk for intakes of whole grains, refined grains, and dietary fiber. METHODS: We pooled individual data from 574,726 participants in 13 cohort studies, 3214 of whom developed incident BC. HRs, with corresponding 95% CIs, were estimated using Cox regression models stratified on cohort. Dose-response relations were examined using fractional polynomial regression models. RESULTS: We found that higher intake of total whole grain was associated with lower risk of BC (comparing highest with lowest intake tertile: HR: 0.87; 95% CI: 0.77, 0.98; HR per 1-SD increment: 0.95; 95% CI: 0.91, 0.99; P for trend: 0.023). No association was observed for intake of total refined grain. Intake of total dietary fiber was also inversely associated with BC risk (comparing highest with lowest intake tertile: HR: 0.86; 95% CI: 0.76, 0.98; HR per 1-SD increment: 0.91; 95% CI: 0.82, 0.98; P for trend: 0.021). In addition, dose-response analyses gave estimated HRs of 0.97 (95% CI: 0.95, 0.99) for intake of total whole grain and 0.96 (95% CI: 0.94, 0.98) for intake of total dietary fiber per 5-g daily increment. When considered jointly, highest intake of whole grains with the highest intake of dietary fiber showed 28% reduced risk (95% CI: 0.54, 0.93; P for trend: 0.031) of BC compared with the lowest intakes, suggesting potential synergism. CONCLUSIONS: Higher intakes of total whole grain and total dietary fiber are associated with reduced risk of BC individually and jointly. Further studies are needed to clarify the underlying mechanisms for these findings.

Adherence to a Western dietary pattern and risk of bladder cancer: A pooled analysis of 13 cohort studies of the Bladder Cancer Epidemiology and Nutritional Determinants international study.

Little is known about the association of diet with risk of bladder cancer. This might be due to the fact that the majority of studies have focused on single food items, rather than dietary patterns, which may better capture any influence of diet on bladder cancer risk. We aimed to investigate the association between a measure of Western dietary pattern and bladder cancer risk. Associations between adherence to a Western dietary pattern and risk of developing bladder cancer were assessed by pooling data from 13 prospective cohort studies in the "BLadder cancer Epidemiology and Nutritional Determinants" (BLEND) study and applying Cox regression analysis. Dietary data from 580 768 study participants, including 3401 incident cases, and 577 367 noncases were analyzed. A direct and significant association was observed between higher adherence to a Western dietary pattern and risk of bladder cancer (hazard ratio (HR) comparing highest with lowest tertile scores: 1.54, 95% confidence interval (CI): 1.37, 1.72; P-trend = .001). This association was observed for men (HR comparing highest with lowest tertile scores: 1.72; 95% CI: 1.51, 1.96; P-trend = .001), but not women (P-het = .001). Results were consistent with HR above 1.00 after stratification on cancer subtypes (nonmuscle-invasive and muscle-invasive bladder cancer). We found evidence that adherence to a Western dietary pattern is associated with an increased risk of bladder cancer for men but not women.

Fruit consumption and the risk of bladder cancer: A pooled analysis by the Bladder Cancer Epidemiology and Nutritional Determinants Study.

While the association between fruit consumption and bladder cancer risk has been extensively reported, studies have had inadequate statistical power to investigate associations between types of fruit and bladder cancer risk satisfactorily. Fruit consumption in relation to bladder cancer risk was investigated by pooling individual data from 13 cohort studies. Cox regression models with attained age as time scale were used to estimate hazard ratios (HRs) for intakes of total fruit and citrus fruits, soft fruits, stone fruits, tropical fruits, pome fruits and fruit products. Analyses were stratified by sex, smoking status and bladder cancer subtype. During on average 11.2 years of follow-up, 2836 individuals developed incident bladder cancer. Increasing fruit consumption (by 100 g/day) was inversely associated with the risk of bladder cancer in women (HR = 0.92; 95% CI 0.85-0.99). Although in women the association with fruit consumption was most evident for higher-risk nonmuscle invasive bladder cancer (NMIBC; HR = 0.72; 95% CI 0.56-0.92), the test for heterogeneity by bladder cancer subtype was nonsignificant (P-heterogeneity = .14). Increasing fruit consumption (by 100 g/day) was not associated with bladder cancer risk in men (HR = 0.99; 95% CI 0.94-1.03), never smokers (HR = 0.96; 95% CI 0.88-1.05), former smokers (HR = 0.98; 95% CI 0.92-1.05) or current smokers (HR = 0.95; 95% CI 0.89-1.01). The consumption of any type of fruit was not found to be associated with bladder cancer risk (P values > .05). Our study supports no evidence that the consumption of specific types of fruit reduces the risk of bladder cancer. However, increasing total fruit consumption may reduce bladder cancer risk in women.

Coffee consumption and risk of bladder cancer: a pooled analysis of 501,604 participants from 12 cohort studies in the BLadder Cancer Epidemiology and Nutritional Determinants (BLEND) international study.

Recent epidemiological studies have shown varying associations between coffee consumption and bladder cancer (BC). This research aims to elucidate the association between coffee consumption and BC risk by bringing together worldwide cohort studies on this topic. Coffee consumption in relation to BC risk was examined by pooling individual data from 12 cohort studies, comprising of 2601 cases out of 501,604 participants. Pooled multivariate hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), were obtained using multilevel Weibull regression models. Furthermore, dose-response relationships were examined using generalized least squares regression models. The association between coffee consumption and BC risk showed interaction with sex (P-interaction < 0.001) and smoking (P-interaction = 0.001). Therefore, analyses were stratified by sex and smoking. After adjustment for potential confounders, an increased BC risk was shown for high (> 500 ml/day, equivalent to > 4 cups/day) coffee consumption compared to never consumers among male smokers (current smokers: HR = 1.75, 95% CI 1.27-2.42, P-trend = 0.002; former smokers: HR = 1.44, 95% CI 1.12-1.85, P-trend = 0.001). In addition, dose-response analyses, in male smokers also showed an increased BC risk for coffee consumption of more than 500 ml/day (4 cups/day), with the risk of one cup (125 ml) increment as 1.07 (95% CI 1.06-1.08). This research suggests that positive associations between coffee consumption and BC among male smokers but not never smokers and females. The inconsistent results between sexes and the absence of an association in never smokers indicate that the associations found among male smokers is unlikely to be causal and is possibly caused by residual confounding of smoking.

An inverse association between the Mediterranean diet and bladder cancer risk: a pooled analysis of 13 cohort studies.

PURPOSE: The role of diet in bladder carcinogenesis has yet to be established. To date most studies have investigated dietary components individually, rather than as dietary patterns, which may provide stronger evidence for any influence of diet on bladder carcinogenesis. The Mediterranean diet has been associated with many health benefits, but few studies have investigated its association with bladder cancer risk. METHODS: We investigated the potential association between the Mediterranean diet score (MDS) and risk of developing bladder cancer by pooling 13 prospective cohort studies included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study and applying a Cox regression analysis. RESULTS: Dietary data from 646,222 study participants, including 3639 incident bladder cancer cases, were analysed. We observed an inverse association between Mediterranean diet and bladder cancer risk (HRhigh 0.85 [95% CI 0.77, 0.93]). When stratifying the results on non-muscle-invasive or muscle-invasive disease or sex the association remained similar and the HR estimate was consistently below 1.00 both for medium and high adherence to the Mediterranean diet. A consistent association was observed when disregarding fat or alcohol intake. CONCLUSION: We found evidence that adherence to the Mediterranean diet was associated with reduced risk of developing bladder cancer, suggesting a positive effect of the diet as a whole and not just one component.

Intake of milk and other dairy products and the risk of bladder cancer: a pooled analysis of 13 cohort studies.

BACKGROUND: Inconsistent associations between milk and other dairy product consumption and bladder cancer (BC) have been reported. We aimed to investigate possible associations with BC risk for total and individual dairy products by bringing together the world's data on this topic. METHODS: Thirteen cohort studies, included in the BLadder cancer Epidemiology and Nutritional Determinants (BLEND) study, provided data for 3590 BC cases and 593,637 non-cases. Associations between milk and other dairy product consumption and BC risk were investigated using Cox proportional hazard regression analyses stratified by study center and adjusted for potential confounders. RESULTS: Overall, total 'other' dairy product consumption was not associated with BC risk (HR comparing highest with lowest tertile: 0.97 (95% CI: 0.87-1.07; ptrend = 0.52) and likewise no association was observed for either liquid milk, processed milk, cream, cheese or icecream. However, an inverse association was observed between yoghurt consumption and BC risk when comparing those in the moderate (25-85 g/day) and high categories (>85 g/day) with non-consumers, with multivariate HR of 0.85 (95% CI: 0.75-0.96) and 0.88 (95% CI: 0.78-0.98), respectively. CONCLUSIONS: We found no evidence of association between either total or individual dairy products and BC risk, but suggestive evidence that consumption of yoghurt may be associated with a decreased risk.

Dietary Intake of Nutrients Involved in One-Carbon Metabolism and Risk of Gastric Cancer: A Prospective Study.

Dietary intakes of B vitamins and other components involved in one-carbon metabolism, which is necessary for DNA replication, DNA repair, and regulation of gene expression, may be associated with carcinogenesis. We investigated associations between intakes of 11 nutrients (thiamine, riboflavin, niacin, pantothenic acid, vitamin B6, biotin, folate, vitamin B12, methionine, choline, and betaine) and gastric cancer risk. A total of 159 incident gastric cancer cases were identified from the Melbourne Collaborative Cohort Study (N = 41,513) and matched with 159 controls on year of birth, sex, and country of birth using incidence density sampling. Dietary intakes of nutrients were estimated at baseline (1990-1994) using a 121-item food frequency questionnaire. Odds ratios (ORs) and 95% confidence intervals were estimated using conditional logistic regression models adjusting for Helicobacter pylori infection, and other potential confounders. We observed a positive association between intake of niacin and overall gastric cancer risk (OR = 1.33, 95%CI: 1.01-1.75 per SD increment). For thiamine, heterogeneity by subtype (cardia and non-cardia) was found (Phet = 0.05), with weak evidence of an inverse association with cardia cancer risk. Our results do not support increasing intakes of B vitamins or other nutrients involved in one-carbon metabolism to reduce gastric cancer risk in a well-nourished population.

Circulating concentrations of B group vitamins and urothelial cell carcinoma.

B-group vitamins, as components of the one carbon metabolism pathway, are involved in DNA synthesis, repair and methylation. Our aim was to investigate associations between circulating plasma levels of B vitamins and urothelial cell carcinoma (UCC). We conducted a nested case-control study of UCC within the Melbourne Collaborative Cohort Study. B vitamins were measured in pre-diagnostic plasma samples. Conditional logistic regression was used to estimate odds ratios (OR) for UCC risk associated with circulating B vitamins in 363 matched cases and controls. In a case-only analysis (N = 390), hazard ratios (HR) for overall survival associated with plasma B vitamins were estimated using Cox regression. There were no strong associations between UCC risk and pre-diagnostic levels of plasma B vitamins. No heterogeneity in UCC risk was observed by subtype (invasive or superficial), sex, smoking status or alcohol intake. There was no heterogeneity by country of birth for most B vitamins, except for folate (p-homogeneity = 0.03). In UCC cases, there were no strong associations between plasma B vitamins and overall survival. We found no associations between pre-diagnostic plasma concentrations of B-group vitamins and UCC risk or survival.

Dietary intake of one-carbon metabolism nutrients and DNA methylation in peripheral blood.

Background: Folate and other one-carbon metabolism nutrients are essential to enable DNA methylation to occur, but the extent to which their dietary intake influences methylation in adulthood is unclear. Objective: We assessed associations between dietary intake of these nutrients and DNA methylation in peripheral blood, overall and at specific genomic locations. Design: We conducted a cross-sectional study using baseline data and samples from 5186 adult participants in the Melbourne Collaborative Cohort Study (MCCS). Nutrient intake was estimated from a food-frequency questionnaire. DNA methylation was measured by using the Illumina Infinium HumanMethylation450 BeadChip array (HM450K). We assessed associations of intakes of folate, riboflavin, vitamins B-6 and B-12, methionine, choline, and betaine with methylation at individual cytosine-guanine dinucleotides (CpGs), and with median (genome-wide) methylation across all CpGs, CpGs in gene bodies, and CpGs in gene promoters. We also assessed associations with methylation at long interspersed nuclear element 1 (LINE-1), satellite 2 (Sat2), and Arthrobacter luteus restriction endonuclease (Alu) repetitive elements for a subset of participants. We used linear mixed regression, adjusting for age, sex, country of birth, smoking, energy intake from food, alcohol intake, Mediterranean diet score, and batch effects to assess log-linear associations with dietary intake of each nutrient. In secondary analyses, we assessed associations with low or high intakes defined by extreme quintiles. Results: No evidence of log-linear association was observed at P < 10-7 between the intake of one-carbon metabolism nutrients and methylation at individual CpGs. Low intake of riboflavin was associated with higher methylation at CpG cg21230392 in the first exon of PROM1 (P = 5.0 × 10-8). No consistent evidence of association was observed with genome-wide or repetitive element measures of methylation. Conclusion: Our findings suggest that dietary intake of one-carbon metabolism nutrients in adulthood, as measured by a food-frequency questionnaire, has little association with blood DNA methylation. An association with low intake of riboflavin requires replication in independent cohorts. This study was registered at http://www.clinicaltrials.gov as NCT03227003.

Dietary intake of nutrients involved in one-carbon metabolism and risk of urothelial cell carcinoma: A prospective cohort study.

Nutrients involved in one-carbon metabolism may play a role in carcinogenesis through DNA replication, repair and methylation mechanisms. Most studies on urothelial cell carcinoma (UCC) have focused on folate. We sought to examine the association between B-group vitamins and methionine intake and UCC risk, overall and by subtype, and to test whether these associations are different for population subgroups whose nutritional status may be compromised. We followed participants in the Melbourne Collaborative Cohort Study (N = 41,513) for over 20 years and observed 500 UCC cases (89% originating in the bladder; superficial: 279, invasive: 221). Energy-adjusted dietary intakes of B vitamins (B1, B2, B3, B5, B6, B8, B9 and B12) and methionine were estimated from a 121-item food frequency questionnaire administered at baseline (1990-1994), using the residuals method. We used Cox regression models to compute hazard ratios (HRs) of UCC risk per standard deviation (SD) of log-transformed nutrient intakes and 95% confidence intervals, adjusted for potential confounders. We investigated associations by tumor subtype, and tested interactions with sex, country of birth, smoking and alcohol drinking. The risk of UCC appeared not to be associated with intake of B-group vitamins or methionine, and findings were consistent across tumor subtypes and across demographic and lifestyle characteristics of the participants. A potential interaction between vitamin B1 and alcohol drinking was observed (all participants: HR per 1 SD = 0.99 (0.91-1.09), never drinkers: HR = 0.81 (0.69-0.97), p-interaction = 0.02), which needs to be confirmed by other studies. Our findings do not indicate that dietary intake of nutrients involved in one-carbon metabolism are associated with UCC risk.

Selenium for preventing cancer.

BACKGROUND: This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. OBJECTIVES: To gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. SEARCH METHODS: We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. DATA COLLECTION AND ANALYSIS: We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. MAIN RESULTS: We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation. AUTHORS' CONCLUSIONS: Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.

Genome-wide measures of DNA methylation in peripheral blood and the risk of urothelial cell carcinoma: a prospective nested case-control study.

BACKGROUND: Global DNA methylation has been reported to be associated with urothelial cell carcinoma (UCC) by studies using blood samples collected at diagnosis. Using the Illumina HumanMethylation450 assay, we derived genome-wide measures of blood DNA methylation and assessed them for their prospective association with UCC risk. METHODS: We used 439 case-control pairs from the Melbourne Collaborative Cohort Study matched on age, sex, country of birth, DNA sample type, and collection period. Conditional logistic regression was used to compute odds ratios (OR) of UCC risk per s.d. of each genome-wide measure of DNA methylation and 95% confidence intervals (CIs), adjusted for potential confounders. We also investigated associations by disease subtype, sex, smoking, and time since blood collection. RESULTS: The risk of superficial UCC was decreased for individuals with higher levels of our genome-wide DNA methylation measure (OR=0.71, 95% CI: 0.54-0.94; P=0.02). This association was particularly strong for current smokers at sample collection (OR=0.47, 95% CI: 0.27-0.83). Intermediate levels of our genome-wide measure were associated with decreased risk of invasive UCC. Some variation was observed between UCC subtypes and the location and regulatory function of the CpGs included in the genome-wide measures of methylation. CONCLUSIONS: Higher levels of our genome-wide DNA methylation measure were associated with decreased risk of superficial UCC and intermediate levels were associated with reduced risk of invasive disease. These findings require replication by other prospective studies.