Increasing evidence shows that inflammation plays critical roles in the tumorigenesis of bladder cancer. Fibroblast growth factor 12 (FGF12), a kind of inflammatory cytokine, is located in the region of 3q28 that has been demonstrated to be a bladder cancer risk locus by genome wide association study (GWAS). In this study, we aimed to investigate the association of GWAS signal rs710521 and rs884309 and rs1464938 in the promoter of FGF12 with the risk of bladder transitional cell carcinoma (TCC). The polymorphisms were analyzed by using a Taqman assay in 331 TCC patients and 516 age-, gender-, and ethnicity-matched controls. The expression levels of FGF12 mRNA were examined in TCC and non-cancerous normal tissues by using quantitative real-time PCR and the luciferase activity was determined by using the Dual-Luciferase Assay System. The rs1464938 AA genotype and A allele were associated with a significantly increased risk of TCC (AA vs. GG: adjusted OR = 2.54, 95% CI, 1.49-4.35, P < 0.001; AA vs. AG/GG: adjusted OR = 2.25, 95% CI, 1.36-3.71, P = 0.002; A vs. G: adjusted OR = 1.44, 95% CI, 1.15-1.80, P = 0.001, respectively). Haplotype analysis showed that rs884309G- rs1464938A haplotype was associated with an increased risk of TCC (OR = 1.61, 95% CI, 1.23-2.11, P = 0.001). Functional analysis showed that the rs1464938 AG/AA genotypes exhibited higher levels of FGF12 mRNA in TCC tissues and the rs1464938 A allele enhanced FGF12 promoter activity (P < 0.05). These findings suggest that the rs1464938 A allele at the 3q28 locus contribute to the development of TCC by regulating FGF12 expression levels.

中文翻译：

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成纤维细胞生长因子 12 启动子中的功能性变异 rs1464938 与膀胱移行细胞癌的风险增加有关

越来越多的证据表明炎症在膀胱癌的肿瘤发生中起着关键作用。成纤维细胞生长因子 12 (FGF12) 是一种炎症细胞因子，位于 3q28 区域，已被全基因组关联研究 (GWAS) 证明是膀胱癌风险位点。在本研究中，我们旨在研究 FGF12 启动子中的 GWAS 信号 rs710521、rs884309 和 rs1464938 与膀胱移行细胞癌 (TCC) 风险的关联。通过在 331 名 TCC 患者和 516 名年龄、性别和种族匹配的对照中使用 Taqman 检测分析多态性。FGF12 mRNA 在 TCC 和非癌正常组织中的表达水平通过实时定量 PCR 检测，荧光素酶活性通过双荧光素酶检测系统测定。rs1464938 AA 基因型和 A 等位基因与 TCC 风险显着增加相关（AA 与 GG：调整后的 OR = 2.54，95% CI，1.49-4.35，P < 0.001；AA 与 AG/GG：调整后的 OR = 2.25 , 95% CI, 1.36-3.71, P = 0.002; A vs. G: 调整后的 OR = 1.44, 95% CI, 1.15-1.80, P = 0.001)。单倍型分析表明，rs884309G-rs1464938A 单倍型与 TCC 风险增加相关（OR = 1.61，95% CI，1.23-2.11，P = 0.001）。功能分析表明，rs1464938 AG/AA 基因型在 TCC 组织中表现出更高水平的 FGF12 mRNA，并且 rs1464938 A 等位基因增强了 FGF12 启动子活性（P < 0.05）。这些发现表明 3q28 位点的 rs1464938 A 等位基因通过调节 FGF12 表达水平促进 TCC 的发展。