Metabolic factors and bladder cancer risk and mortality. Studies to approach causal associations and interactions with smoking and genetic variants

Abstract: Urothelial bladder cancer (BC) is one of the most common cancers in developed countries. It has one of the highest recurrence rates among solid tumors, resulting in regular treatment and follow-up, making it one of the most expensive cancers to treat, and a significant public health burden. Derangement of metabolic factors such as body mass index (BMI), blood pressure (BP), glucose, triglycerides (TG) and cholesterol (TC) has resulted inglobal epidemics such as obesity, hypertension, diabetes and dyslipidemia, which collectively impact cardiovascular disease and certain cancers. Previous studies investigating the link between metabolic factors andBC have shown inconsistent results, furthermore, additive and multiplicative interactions, which may inform biological mechanisms, are rarely investigated in such studies.This thesis aimed to clarify the link between metabolic factors and BC, especially BP, by investigating the association between metabolic factors and BC risk (total, and separately into sub-groups based on tumor characteristics) and BC-specific mortality, using conventional survival analysis and additionally for BP, MendelianRandomization (MR) analysis, and to assess additive and multiplicative interaction with smoking and BC genetic variants in such associations.In studies that spanned several prospective cohorts, we found, as main findings among men: a positive association between systolic BP (SBP) and muscle-invasive BC (MIBC)/aggressive urothelial cancer risk (paper Ⅰ-Ⅳ), and a stronger association among never-smokers, both in conventional survival analysis and MR analysis of a Swedish cohort, a positive association between BMI, TG and TC and non-muscle invasive BC (NMIBC) risk, and a positive association between SBP and TG and risk of BC-specific mortality. Among women (paper Ⅰ), we found aninverse association between BMI and total BC risk, a positive association between glucose and MIBC risk, and a positive association between TG and risk of BC-specific mortality. In the interaction analysis among men, SBP and DBP did not interact with NAT2 in relation to total BC risk; however, SBP and a genetic score for BC positively interacted on an additive scale, in relation to MIBC risk.In conclusion, aberrations in metabolic factors was associated with BC outcomes; the associations differed depending on the sub-group of population and the specific outcome being investigated. Among men, SBP consistently showed a positive association with MIBC risk, furthermore, SBP and the genetic risk of BC positively interacted on an additive scale. The thesis highlights the importance of investigating associations in specific subgroups of the population and specific BC outcomes, and assessing interaction to explore potential biological mechanisms and inform public health.