Genetic variants in splicing factor genes and susceptibility to bladder cancer

Background: Genome-wide association studies have demonstrated that genetic variants are closely related to tumorigenesis and progression of cancer. However, the correlation between genetic variants in splicing factor genes and bladder cancer susceptibility remains unclear. Method: A case-control study with 580 cases of bladder cancer and 1,101 controls was conducted to explore the association of single-nucleotide polymorphisms (SNPs) in splicing factors with bladder cancer susceptibility by logistic regression models, and multiple testing errors were justified by the false discovery rate (FDR) method. Next, we used the Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) datasets to further analyze the differential expression of candidate genes. Results: We found that rs978416 G>A in RBFOX3 contributed to a reduced risk of bladder cancer [adjusted odds ratio (OR) = 0.72, 95% confidence internal (CI) = 0.62-0.84, P = 3.54 x 10-5], especially in individuals who never smoked (P = 7.83 x 10-5). Stratified analysis showed that the protective effect of rs978416 was more significant in the subgroup of low grade and non-muscle invasive bladder cancer. Furthermore, the RBFOX3 mRNA expression was decreased in bladder tumor tissues. However, the relatively high expression of RBFOX3 was related to a higher bladder cancer stage. Conclusions: Our findings indicated that SNP rs978416 G>A in RBFOX3 may be related to bladder cancer predisposition in Chinese population and might serve as a novel biomarker for bladder cancer risk.