Background
Patients who are diagnosed with non-muscle invasive bladder cancer (NMIBC) have a high chance of a bladder tumour recurrence. Importantly, this recurrent tumour may progress into a more lethal muscle- invasive bladder tumour. That is why the treatment and follow-up program for NMIBC patients is intensive and burdensome. Currently, it is not well understood which biological processes affect the chances of tumour recurrence and progression. The relation between the body size measure body mass index (BMI) and NMIBC outcome has been studied in a number of NMIBC patient groups but with inconclusive results. Also, there are almost no studies in NMIBC that look into other measures of body size and body-size related blood measurements like inflammation levels.
Aims and Objectives
We aimed to investigate the causal relation between body size measures BMI and Waist- Hip-Ratio (WHR)) and risk of NMIBC recurrence and progression. Secondly, we investigated the causal association of blood levels of insulin, adiponectin, leptin, insulin-like growth factor 1 (IGF-1) and C-reactive protein (CRP), which are markers of metabolic and inflammatory activity, and risk of NMIBC recurrence and progression.
How the study was carried out
One could study the associations mentioned above by directly measuring body size and inflammatory and metabolic blood levels in a group of NMIBC patients. However, it is then difficult to draw conclusions on causality of the associations due to the potentially disturbing effects of other (unmeasured) variables (e.g. smoking status). To prevent these so-called biased or invalid results, we measured body size measures and blood-based markers indirectly, by measuring the germline, heritable DNA variants that affect them. This is a so-called Mendelian randomization study, referring to the fact that this type of study mimics the randomized controlled trial, the gold-standard study design to obtain strong evidence on causal associations. We included a large number of NMIBC patients in our analyses (N=5,008). Relevant data on germline DNA variation and recurrence and progression were already available via existing international collaborations. We applied two different, well-established Mendelian randomization analyses.
Key findings
We did not observe associations between BMI and WHR and NMIBC recurrence and progression. We also did not observe associations between BMI, WHR and NMIBC outcomes in subgroups of men and women and subgroups of patients treated and not treated with BCG immunotherapy. However, we found a relation between higher blood levels of insulin and leptin and an increased risk of recurrence, but no relation with risk of progression. Finally, our results showed that higher levels of CRP and IGF-1 were related to a decreased risk of recurrence, but we however actually expected an increased risk based on current knowledge.
Conclusions
The conclusions from our work will influence researchers and clinicians in the field of bladder cancer to not focus on BMI and WHR as main modifiable targets to improve a patient’s recurrence or progression risk. While future research investigating if and how levels of insulin and leptin affect outcome in patients with NMIBC is important.
We will efficiently use existing genetic data to generate evidence on the potential relation between body size and outcome in non-muscle invasive bladder cancer and create insights into its underlying mechanisms.
Dr Sita Vermeulen
