Abstract
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.
Highlights
IntroductionUrothelial cell carcinoma (UCC) includes tumours of the renal pelvis, the ureter, urinary bladder and proximal urethra, with about 90% of these originating in the urothelium of the bladder. 1 While age, sex, smoking, and occupational exposure to chemicals are established risk factors for the development of UCC, 2 the role of dietary factors remains unclear. 3, 4 it is biologically plausible that dietary factors are involved in the aetiology of UCC due to their opportunity for contact with the urothelium, 5 the World Cancer Research Fund’s (WCRF) Second Expert Report in 2007 found that the evidence was too limited to conclude that any food or nutrient was directly associated with the risk of bladder cancer, but limited evidence was identified suggesting that consumption of folate and milk, rich in vitamin B2 and B12, are associated with reduced risk, and drinking water contaminated with arsenic is associated with increased risk of developing bladder cancer. 6 Similar conclusions were reached by the 2015 WCRF Systematic Literature Review Continuous Update Project Report. 7 Folate (vitamin B9), which is one of several B group vitamins that are water-soluble and excreted via the urinary tract, may modify arsenic metabolism. 8B-group vitamins such as folate and vitamins B2, B6 and B12 are present in a wide range of foods such as cereals, meat, fruit and vegetables, and are involved in key cellular functions such as the metabolism of energy providing macronutrients. 9, These vitamins form part of the one-carbon metabolism pathway and, as such, play a key role in DNA synthesis, repair and methylation, and potentially influence carcinogenesis
It is biologically plausible that dietary factors are involved in the aetiology of Urothelial cell carcinoma (UCC) due to their opportunity for contact with the urothelium, 5 the World Cancer Research Fund’s (WCRF) Second Expert Report in 2007 found that the evidence was too limited to conclude that any food or nutrient was directly associated with the risk of bladder cancer, but limited evidence was identified suggesting that consumption of folate and milk, rich in vitamin B2 and B12, are associated with reduced risk, and drinking water contaminated with arsenic is associated with increased risk of developing bladder cancer
Moderate intakes of vitamin B6 appeared to be associated with higher risk
Summary
Urothelial cell carcinoma (UCC) includes tumours of the renal pelvis, the ureter, urinary bladder and proximal urethra, with about 90% of these originating in the urothelium of the bladder. 1 While age, sex, smoking, and occupational exposure to chemicals are established risk factors for the development of UCC, 2 the role of dietary factors remains unclear. 3, 4 it is biologically plausible that dietary factors are involved in the aetiology of UCC due to their opportunity for contact with the urothelium, 5 the World Cancer Research Fund’s (WCRF) Second Expert Report in 2007 found that the evidence was too limited to conclude that any food or nutrient was directly associated with the risk of bladder cancer, but limited evidence was identified suggesting that consumption of folate and milk, rich in vitamin B2 and B12, are associated with reduced risk, and drinking water contaminated with arsenic is associated with increased risk of developing bladder cancer. 6 Similar conclusions were reached by the 2015 WCRF Systematic Literature Review Continuous Update Project Report. 7 Folate (vitamin B9), which is one of several B group vitamins that are water-soluble and excreted via the urinary tract, may modify arsenic metabolism. 8B-group vitamins such as folate and vitamins B2, B6 and B12 are present in a wide range of foods such as cereals, meat, fruit and vegetables, and are involved in key cellular functions such as the metabolism of energy providing macronutrients. 9, These vitamins form part of the one-carbon metabolism pathway and, as such, play a key role in DNA synthesis, repair and methylation, and potentially influence carcinogenesis. While there is mounting evidence of a role for these key nutrients in the development of tumours at other sites, the few studies that have investigated associations between B vitamins and risk of UCC have been heterogeneous in design, measures, analyses and findings. A 2014 meta-analysis reported a potential inverse association between folate intake and bladder cancer risk, this association was only evident from retrospective studies and not in prospective studies. 18 One large US case-control study included in the meta-analysis which found no association of bladder cancer risk with folate intake, identified a potential inverse association with vitamin B12 intake. Our secondary aims were to examine potential differences in risk between superficial and invasive disease, and to assess whether associations were more evident for higher-risk groups such as smokers and alcohol drinkers, as these behaviours may alter nutritional status
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