UHRF1BP1: a tumor suppressor gene associated with bladder cancer risk in Han Chinese

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Approximately 20 loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS), which are all common variants. However, little is known about potential contribution of low-frequency and rare variants to bladder cancer susceptibility.


We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify new low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome array data in 1,030 bladder cancer patients and 1,008 controls in the discovery stage using Illumina Human Exome Beadchip. Sequenom MassARRAY and Taqman Probe were used in two replication stages to validate variants identified from the discovery stage. Logistic regression was conducted to evaluate single marker association with bladder cancer risk in an additive model. Gene level-based analysis was applied using the SKAT-O method. In vivo experiments were further performed to determine the function of gene selected.


We identified a novel rare coding variant (rs35356162 of UHRF1BP1: OR=4.332, P=3.62E-07) that increased bladder cancer risk in Han Chinese populations, along with a common variant rs3736001 (OR=1.265, P=5.00E-06) in the previously reported gene PSCA by GWAS. Gene-level analysis also showed a significant associations of both UHRF1BP1 (P=4.47E-03) and PSCA (P=1.30E-03) with bladder cancer risk. Additional experiments revealed that down-regulation of UHRF1BP1 promoted migration and invasion through epithelial-mesenchymal transition as well as increased proliferation in bladder cancer cell lines.


A rare variant of UHRF1BP1, rs35356162, increases bladder cancer risk in Han Chinese populations and UHRF1BP1 acts as a tumor suppressor in bladder cancer development and progression.

Funding: National Natural Science Foundation of China (Grant No. NSFC 81272837)