title: A functional variant in TP63 at 3q28 associated with bladder cancer risk by creating an miR-140-5p binding site.
abstract: 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.
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Meilin
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Mulong
authors.initials: M
authors.lastname: Du
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Ma
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chu
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lv
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Dingwei
authors.initials: D
authors.lastname: Ye
authors.affiliation: Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Jianming
authors.initials: J
authors.lastname: Guo
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Gu
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Guowei
authors.initials: G
authors.lastname: Xia
authors.affiliation: Department of Urology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.affiliation: Department of Urology, Jiangsu Province Hospital of TCM, Nanjing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Urology, The Huai-An First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
authors.forename: Guangbo
authors.initials: G
authors.lastname: Fu
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Na
authors.initials: N
authors.lastname: Tong
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Changjun
authors.initials: C
authors.lastname: Yin
authors.affiliation: Fudan Institute of Urology, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001665:Binding Sites; D002874:Chromosome Mapping; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D035683:MicroRNAs; C544302:Mirn140 microRNA, human; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins
keywords: 3q28; bladder cancer; fine mapping; genetic variants