Carcinogenesis Advance Access originally published online on August 5, 2008
Carcinogenesis 2008 29(10):1973-1978; doi:10.1093/carcin/bgn183
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Genetic variants in RUNX3 and risk of bladder cancer: a haplotype-based analysis
1 Cancer Center
2 Department of Molecular and Genetic Toxicology
3 Department of Epidemiology and Biostatistics, Nanjing Medical University, Nanjing 210029, China
4 Department of Urology, The Huai-An First Affiliated Hospital, Nanjing Medical University, Huai-An 223300, China
* To whom correspondence should be addressed. Department of Molecular and Genetic Toxicology, School of Public Health, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, China. Tel: +86 25 86862937; Fax: +86 25 86527613; Email: zdzhang{at}njmu.edu.cn
Transforming growth factor-β (TGF-β) is a multifunctional growth factor that plays important roles in many biological processes, whereas RUNX3 is a target of TGF-β-mediated tumor suppressor pathway. In humans, RUNX3 inactivation may lead to the cancer development, including bladder cancer. To determine whether the RUNX3 polymorphisms are associated with risk of bladder cancer, we conducted a case–control study of 368 bladder cancer patients and 368 cancer-free controls to assess the associations between the RUNX3 tagging single-nucleotide polymorphisms (tSNPs) and bladder cancer risk. In the single-locus analysis, we found a significantly increased risk of bladder cancer associated with the SNP7 rs760805 AA genotype (adjusted odds ratio = 1.97, 95% confidence interval = 1.44–2.69), compared with the AT/TT genotype. Haplotype-based association analysis revealed that the increased risk of bladder cancer was significantly associated with two haplotypes TATCCCAAAA (2.37, 1.16–4.83) and AGCTTGAGAG (2.70, 1.08–6.72) that included the rs760805 A allele. Multifactor dimensionality reduction (MDR) analysis identified a significant more than multiplicative interaction between the SNP7 rs760805 AA and smoking and an additive interaction between the SNP3 rs11249206 TT and smoking on bladder cancer risk. The SNP3 rs11249206, SNP5 rs1395621, SNP7 rs760805, SNP8 rs2236852 and the trichotomized cumulative smoking were the five factors best predicted by the MDR models. When the variables were combined and dichotomized and fitted into the MDR model, the subjects carrying the combined risk stratum had a significantly increased risk for bladder cancer (6.37, 4.57–8.87, P = 7.03 x 10–28). These results suggested that the genetic variants in RUNX3 may modulate the risk of bladder cancer.
Abbreviations: CI, confidence interval; CVC, cross-validation consistency; LD, linkage disequilibrium; MDR, multifactor dimensionality reduction; OR, odds ratio; SNP, single-nucleotide polymorphism; TGF-β, transforming growth factor-β; tSNP, tagging single-nucleotide polymorphism
Received July 17, 2008; revised July 31, 2008; accepted August 1, 2008.