Association between lung cancer and bladder cancer risk: a bidirectional Mendelian randomization study

Abstract Background The second primary cancer (SPC) poses a significant threat to lung cancer survivors, with bladder cancer being one of the most common SPCs. The relationship between lung cancer and bladder cancer has remained unclear. In this study, we aimed to evaluate the causal effect between these two cancers through bidirectional two-sample Mendelian randomization (MR) analysis. Methods Genetic instruments associated with lung cancer and its subgroups were derived from the International Lung Cancer Consortium (ILCCO), while the data of bladder cancer was obtained from the FinnGen biobank. To estimate the causal relationship, we employed inverse-variance weighted (IVW) method, MR-Egger, and weighted-median method. Additionally, we conducted Cochran's Q test, MR-Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and leave-one-out analysis to assess potential pleiotropy effects. Results Our analysis revealed that genetically overall lung cancer increased the risk of bladder cancer based on the IVW and weighted median method. However, subgroup analysis showed no causal relationship between LUSC or LUAD and bladder cancer. In the reverse MR analysis, we found no evidence of any causal relationship between bladder cancer and overall lung cancer. Subgroup analysis suggested that bladder cancer increased the risk of LUSC. The assessment of heterogeneity and pleiotropy provided further support for the robustness and validity of these MR results. Conclusions Our study provided evidence in support of causality between lung cancer and bladder cancer in individuals of European ancestry. We should focus on SPC-bladder cancer or SPC-LUSC to intervene in time.