In this large case‐control study, we evaluated the association between energy balance and risk of bladder cancer and assessed joint effects of genetic variants in the mTOR pathway genes with energy balance on bladder cancer risk. The energy balance related variables were total energy intake, physical activity and body mass index (BMI). The study included 803 Caucasian bladder cancer patients and 803 healthy Caucasian controls matched to cases by age (± 5 years) and gender. High energy intake as defined by the highest tertile of energy intake in controls (OR=1.60; 95% CI=1.23–2.09) and low physical activity as defined by the lowest tertile of physical activity in controls (OR=2.82; 95% CI=2.10–3.79) were each associated with significantly increased risk of bladder cancer with dose‐response trends (all P for trend<0.001). However, obesity (BMI > 30) was not associated with bladder cancer risk. When stratified by smoking status, the increased risk conferred by high energy intake was observed in ever smokers only and there was a significant interaction between smoking status and energy intake (P for interaction=0.033). Analysis of genetic variants in the mTOR pathway showed that among 222 SNPs, 28 SNPs located in 6 genes of mTOR pathway (AKT3, RHEB, RPS6KA5, IRS2, TSC2 and RAPTOR) were significantly associated with bladder cancer risk. The minor allele frequency of the significant SNPs ranged from 0.09 to 0.48 in controls. To further elucidate the association between energy balance and bladder cancer, we stratified the analysis of energy balance by genetic variants in the mTOR pathway. We found that the risk associated with high energy intake and low physical activity was only evident among subjects carrying a high number of unfavorable genotypes in the mTOR pathway. For example, there was no significant association between physical activity and bladder cancer or energy intake and bladder cancer among subjects carrying low number of unfavorable genotypes (0–5 unfavorable genotypes). However, among subjects carrying 10 or more unfavorable genotypes, the risk from low physical activity was 3.37 (95% CI= 2.08 to 5.46; P<0.001) and the risk from high energy intake was 1.84 (95% CI=1.20 to 2.81; P=0.005). Moreover, when physical activity, energy intake and genetic variants of the mTOR pathway were analyzed jointly, the study population was clearly stratified into a range of low to high risk subgroups as defined energy balance status. Compared to subjects within the most favorable energy balance category (low energy intake, intensive physical activity, low number of unfavorable genotypes), subjects located in the worst energy balance category (high energy intake, low physical activity, and carrying ten or more unfavorable genotypes) had 10.04‐fold increased risk of bladder cancer (95% CI=2.77 to 36.47). This is the first study to report joint effects of energy balance and mTOR pathway genes in bladder cancer. Our results strongly support that physical activity, energy intake and genetic variants in the mTOR pathway jointly influence bladder cancer susceptibility and these results have implications in bladder cancer prevention.
Citation Information: Cancer Prev Res 2010;3(1 Suppl):B114.