Castillejo Adela, Rothman Nathaniel, Murta-Nascimento Cristiane, Malats Núria, García-Closas Montserrat, Gómez-Martínez Angeles, Lloreta Josep, Tardón Adonina, Serra Consol, García-Closas Reina, Chanock Stephen, Silverman Debra T, Dosemeci Mustafa, Kogevinas Manolis, Carrato Alfredo, Soto José Luis, Real Francisco X
Grupo de Oncología Molecular, Hospital General Universitario de Elche, Elche, Spain.
Int J Cancer. 2009 Feb 1;124(3):608-13. doi: 10.1002/ijc.24013.
The transforming growth factor-beta (TGF-beta) signalling pathway plays an important role in tumor development and progression. We aimed at analyzing whether 7 different common variants in genes coding for 2 key members of the TGF-beta signalling pathway (TGFB1 and TGFBR1) are associated with bladder cancer risk and prognosis. A total of 1,157 cases with urothelial cell carcinoma of the bladder and 1,157 matched controls where genotyped for 3 single nucleotide polymorphisms (SNPs) in TGFB1 (rs1982073, rs1800472, rs1800471) and an additional 3 SNPs and 1 indel polymorphism in TGFBR1 (rs868, rs928180, rs334358 and rs11466445, respectively). In the case-control study, we estimated odds ratios and 95% confidence intervals for each individual genetic variant using unconditional logistic regression adjusting for age, gender, study area and smoking status. Survival analysis was performed using the Kaplan-Meier method and Cox models. The endpoints of interest were tumor relapse, progression and death from bladder cancer. All the SNPs analyzed showed a similar distribution among cases and controls. The distribution of the TGFBR1*6A allele (rs11466445) was also similar among cases and controls, indicating no association with bladder cancer risk. Similarly, none of the haplotypes was significantly associated with bladder cancer risk. Among patients with muscle-invasive tumors, we found a significant association between TGFBR1-rs868 and disease-specific mortality with an allele dosage effect (p-trend=0.003). In conclusion, the genetic variants analyzed were not associated with an increased risk of bladder cancer. The association of TGFBR1-rs868 with outcome should be validated in independent patient series.
转化生长因子-β（TGF-β）信号通路在肿瘤发生和发展中起重要作用。我们旨在分析TGF-β信号通路的2个关键成员（TGFB1和TGFBR1）编码基因中的7种不同常见变异是否与膀胱癌风险及预后相关。对总共1157例膀胱尿路上皮细胞癌患者和1157例匹配对照进行基因分型，检测TGFB1中的3个单核苷酸多态性（SNP）（rs1982073、rs1800472、rs1800471）以及TGFBR1中的另外3个SNP和1个插入缺失多态性（分别为rs868、rs9,281,80、rs334358和rs11466445）。在病例对照研究中，我们使用无条件逻辑回归，对年龄、性别、研究地区和吸烟状况进行校正，估计每个个体基因变异的比值比和95%置信区间。采用Kaplan-Meier法和Cox模型进行生存分析。感兴趣的终点为肿瘤复发、进展和膀胱癌死亡。所有分析的SNP在病例和对照中的分布相似。TGFBR1*6A等位基因（rs11466445）在病例和对照中的分布也相似，表明与膀胱癌风险无关。同样，没有单倍型与膀胱癌风险显著相关。在肌肉浸润性肿瘤患者中，我们发现TGFBR1-rs868与疾病特异性死亡率之间存在显著关联，且存在等位基因剂量效应（p趋势=0.003）。总之，所分析的基因变异与膀胱癌风险增加无关。TGFBR1-rs868与预后的关联应在独立患者系列中进行验证。
