Wu Junlong, Wang Meilin, Chen Haitao, Xu Jianfeng, Zhang Guiming, Gu Chengyuan, Ding Qiang, Wei Qingyi, Zhu Yao, Ye Dingwei
Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Front Oncol. 2020 Feb 11;10:134. doi: 10.3389/fonc.2020.00134. eCollection 2020.
Seventeen loci have been found to be associated with bladder cancer risk by genome-wide association studies (GWAS) in European population. However, little is known about contribution of low-frequency and rare variants to bladder cancer susceptibility, especially in Eastern population. We performed a three-stage case-control study including 3,399 bladder cancer patients and 4,647 controls to identify low-frequency and rare variants associated with bladder cancer risk in Han Chinese. We examined exome-array data in 1,019 bladder cancer patients and 1,008 controls in discovery stage. Two replication stages were included to validate variants identified. Bonferroni adjustment was performed to define statistical significance. Logistic regression was conducted to evaluate single marker association with bladder cancer risk. We used SKAT-O method to perform gene level-based analysis. We also conduct additional experiments to explore the underlying mechanism of filtered gene(s). We identified a novel rare coding variant (rs35356162 in : G > T, OR = 4.332, = 3.62E-07 < 7.93E-07, Bonferroni cutoff) that increased bladder cancer risk in Han Chinese. Gene-level analysis showed a significant association of ( = 4.47E-03) with bladder cancer risk. Experiments indicated down-regulation of promoted migration and invasion through epithelial-mesenchymal transition in bladder cancer cell lines. The rare variant of , rs35356162, increases bladder cancer risk in Han Chinese and UHRF1BP1 might act as a tumor suppressor in bladder cancer development and progression. Little is known about potential contribution of low-frequency and rare variants to bladder cancer susceptibility. We performed a three-stage case-control study and identified a new rare variant, rs35356162 in , which increased bladder cancer risk in Han Chinese.
通过欧洲人群的全基因组关联研究（GWAS）已发现17个基因座与膀胱癌风险相关。然而，低频和罕见变异对膀胱癌易感性的贡献知之甚少，尤其是在东方人群中。我们进行了一项三阶段病例对照研究，包括3399例膀胱癌患者和4647例对照，以确定与汉族人群膀胱癌风险相关的低频和罕见变异。我们在发现阶段检查了1019例膀胱癌患者和1008例对照的外显子阵列数据。包括两个复制阶段以验证所鉴定的变异。进行Bonferroni校正以定义统计学显著性。进行逻辑回归以评估单个标记与膀胱癌风险的关联。我们使用SKAT-O方法进行基于基因水平的分析。我们还进行了额外的实验以探索筛选出的基因的潜在机制。我们鉴定出一种新的罕见编码变异（位于：rs35356162，G>T，OR = 4.332，= 3.62E-07 < 7.93E-07，Bonferroni临界值），其增加了汉族人群的膀胱癌风险。基因水平分析显示与膀胱癌风险有显著关联（= 4.47E-03）。实验表明，在膀胱癌细胞系中，的下调通过上皮-间质转化促进了迁移和侵袭。的罕见变异rs35356162增加了汉族人群的膀胱癌风险，并且UHRF1BP1可能在膀胱癌的发生和发展中起肿瘤抑制作用。低频和罕见变异对膀胱癌易感性的潜在贡献知之甚少。我们进行了一项三阶段病例对照研究，并鉴定出一个新的罕见变异，即中的rs35356162，其增加了汉族人群的膀胱癌风险。
