Introduction:

Bladder cancer is associated with well-known lifestyle risk factors such as smoking status. In addition, recent studies have highlighted the role of inherited genetic factors in the development of the disease. The objective of this study is to assess the independent and joint effect of polygenic score (PGS) over known lifestyle risk factors for predicting bladder cancer risk in a large prospective cohort of bladder cancer patients derived from the UK Biobank (UKB).

Methods:

Subjects without a bladder cancer diagnosis at the recruitment of the UKB were identified and followed for a diagnosis of bladder cancer. Known lifestyle risk factors at the time of recruitment were collected. In addition, a previously published PGS for bladder cancer based on 24,359 SNPs (PGS000616) was calculated for each subject and grouped into low-, average-, and high-risk based on their PGS deciles (bottom, middle 8, and top decile, respectively). Association of lifestyle risk factors and PGS with incident bladder cancer was tested using the Cox proportional-hazards model adjusting for genetic background [top 10 principal components (PCs)]. Time to incident bladder cancer diagnosis among subjects from the three PGS risk groups was estimated and compared using the Kaplan-Meier method. Association between age at diagnosis and PGS in bladder cancer patients was also tested using multiple linear regression analysis adjusting for age at recruitment.

Results:

Among 484,648 UKB subjects who did not have a bladder cancer diagnosis prior to study recruitment, 3,373 (0.7%) were diagnosed with bladder cancer during an average 12.5 years of follow-up. In a multivariable analysis adjusting for age at recruitment, sex, body mass index (BMI), education level, income, frailty, and lifestyle factors (smoking status, alcohol consumption, physical activity, and healthy diet), higher PGS was significantly associated with increased risk of bladder cancer; hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.14-1.17, p<0.001. Subjects with poor lifestyle risk factors and high PGS risk group had the highest risk for bladder cancer (Table). Among subjects diagnosed with bladder cancer, higher PGS was associated with earlier age at diagnosis in a multivariable analysis; β = -0.30, standard error = 0.02, p<0.001. Similar results were found using the Kaplan-Meier method (Figure).

Conclusion:

In this prospective, observational cohort study using data from the UK Biobank, the PGS was significantly and independently associated with increased risk of bladder cancer. The PRS was also associated with earlier age at diagnosis, suggesting those with increased genetic predisposition to bladder cancer may present earlier. In addition to counseling for smoking cessation and recommendations for a healthy lifestyle, genetic risk should be considered in efforts for screening, prevention, and early detection of bladder cancer. Future validation studies in other racial groups should be performed.

Funding: N/A