AbstractBACKGROUND:Epigenetic silencing of several wingless‐type mouse mammary tumor virus integration site (Wnt) pathway‐related genes has been reported in renal cancer. Except for the T‐cell factor 4 gene TCF4, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, the authors of this report hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer.METHODS:In total, 210 patients (145 men and 65 women) with pathologically confirmed renal cell carcinoma (RCC) and 200 age‐matched and sex‐matched control individuals were enrolled in this study. We genotyped 14 single nucleotide polymorphisms (SNPs) in 6 genes. including Dickkopf 2 (DKK2) (reference SNP identification number 17037102 [rs17037102], rs419558, and rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, and rs2291599), DKK4 (rs2073664), secreted frizzled‐related protein 4 (sFRP4) (rs1802073 and rs1802074), mothers against decapentaplegic homolog (SMAD) family member 7 or SMAD7 (rs12953717), and disheveled associated activator of morphogenesis 2 or DAAM2 (rs6937133 and rs2504106) using polymerase chain reaction‐restriction fragment length polymorphism analysis and direct sequencing in the patients with RCC and in the healthy, age‐matched control group. The relations also were tested between these polymorphisms and clinicopathologic data, including sex, tumor grade, tumor stage, lymph node involvement, distant metastasis, and overall survival.RESULTS:A significant decrease in the frequency of the guanine/adenine (G/A) + A/A genotypes in the DKK3 codon 335 rs3206824 was observed in the patients with RCC compared with the control group. The frequency of the rs3206824 (G/A) A‐rs7396187 (guanine/cytosine [G/C]) C haplotype was significantly lower in patients with RCC compared with other haplotypes. In addition, DKK3 rs1472189 cytosine/thymine (C/T) was associated with distant metastasis, and, DKK2 rs17037102 G‐homozygous patients had a decreased risk for death in multivariate Cox regression analysis.CONCLUSIONS:To the authors' knowledge, this is the first report documenting that DKK3 polymorphisms are associated with RCC and that the DKK2 rs17037102 polymorphism may be a predictor for survival in patients with RCC after radical nephrectomy. Cancer 2009. © 2009 American Cancer Society.