A functional variant in TP63 at 3q28 associated with bladder cancer risk by creating an miR-140-5p binding site

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• 作者：Meilin Wang ; Mulong Du ; Lan Ma ; Haiyan Chu ; Qiang Lv ; Dingwei Ye ; Jianming Guo ; Chengyuan Gu ; Guowei Xia ; Yao Zhu ; Qiang Ding ; Lin Yuan ; Guangbo Fu ; Na Tong ; Chao Qin ; Changjun Yin ; Jianfeng Xu and Zhengdong Zhang
• 关键词：fine mapping ; 3q28 ; genetic variants ; bladder cancer
• 刊名：International Journal of Cancer
• 出版年：2016
• 出版时间：1 July 2016
• 年：2016
• 卷：139
• 期：1
• 页码：65-74
• 全文大小：490K
• ISSN：1097-0215

文摘

The first genome-wide association study (GWAS) for bladder cancer has identified a susceptibility locus at 3q28 in the European ancestry. However, the causal variant at 3q28 remains unknown. We conducted a three-stage fine mapping study to identify potential causal variants in the region. A total of 41 single nucleotide polymorphisms (SNPs) across 120 kb at 3q28 were tested for association with bladder cancer risk among 3,094 bladder cancer cases and 3,738 controls. Resequencing and functional assays were further evaluated. The SNP rs35592567 in the 3′-UTR of TP63 was consistently associated with bladder cancer risk in all three stages. In the combined analysis, the T allele of rs35592567 was significantly associated with a decreased risk for bladder cancer (OR = 0.82, 95% CI = 0.75–0.90, P = 9.797 × 10⁻⁶ in the additive model). Biochemical assays revealed that the T allele reduced the post-transcriptional levels of TP63 mediated by interfering binding efficiency of miR-140-5p. In addition, overexpression of miR-140-5p inhibited bladder cancer cell proliferation and attenuated cell migration, invasion and G1 cell-cycle arrest. Together, these results suggest that rs35592567 in TP63 may be a novel causal variant contributing to the susceptibility to bladder cancer, which provides additional insight into the pathogenesis of bladder carcinogenesis.