Wnt antagonist gene polymorphisms and renal cancer

Abstract

Purpose Epigenetic silencing of several Wnt pathway related genes has been reported in renal cancer. Except for the TCF4 gene, there are no reports regarding Wnt pathway gene polymorphisms in renal cancer. Therefore, we hypothesized that the polymorphisms in Wnt signaling genes may be risk factors for renal cancer. Experimental Design A total of 210 patients (145 male and 65 female) with pathologically confirmed renal cell carcinoma (RCC), and 200 age- and sex-matched control individuals were enrolled in this study. We genotyped 14 SNPs in six genes including DKK2 (rs17037102, rs419558, rs447372), DKK3 (rs3206824, rs11022095, rs1472189, rs7396187, rs2291599), DKK4 (rs2073664), sFRP4 (rs1802073, rs1802074), SMAD7 (rs12953717), DAAM2 (rs6937133, rs2504106) using PCR-RFLP and direct sequencing in RCC and age-matched healthy subjects. We also tested the relationship between these polymorphisms and clinicopathologic data including gender, grade, tumor stage, lymph-node involvement, distant metastasis, and overall survival. Results A significant decrease in the frequency of the G/A+A/A genotypes in the DKK3 codon335 rs3206824 was observed in RCC patients compared with controls. The frequency of the rs3206824 (G/A) A- rs7396187 (G/C) C haplotype was significantly lower in RCC compared with other haplotypes. We also found that DKK3 rs1472189 C/T is associated with distant metastasis and furthermore, DKK2 rs17037102 G homozygous patients had a decreased risk for death by multivariate Cox regression analysis. Conclusions 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 RCC patients after radical nephrectomy.

Association between Polymorphisms in Sclerostin, Dickkopfs and Secreted Frizzled-Related Protein Genes and Bone Mineral Density in Postmenopausal Korean Women

“…Also, the present finding that the DKK3 c.1003A>G polymorphism was not related to BMD supports the notion that DKK3 has no known effect on Wnt signaling [14,15]. With respect to the DKK2 c.437G>A polymorphism, the frequency of the GG genotype (32.6%) was lower than that reported in a Japanese population (53%) [37]. In contrast to the study of Sims et al [28] reporting that the DKK2 c.437G>A polymorphism showed an association with BMD in Australian postmenopausal women, no association between this polymorphism and BMD was noted in the present study.…”

Signaling pathways in renal cell carcinoma

“…The secreted-Frizzled receptor proteins (sFRPs), Dickkopf 2 (DKK2) and Wnt inhibitory factor 1 (WIF-1) are Wnt antagonists and expression of these genes is also silenced by aberrant hypermethylation in RCC. [59][60][61][62][63] Thus, Wnt has a dual role in pathogenesis of RCC. It not only induces transcription through activation of β-catenin, but also stimulates translation and cell growth through activation of the mTOR pathway.…”

A Functional Germline Variant in GLI1 Implicates Hedgehog Signaling in Clinical Outcome of Stage II and III Colon Carcinoma Patients

“…These common DNA-sequence variations may alter the gene function and/or activity, including transcription, translation, or splicing, thereby causing interindividual differences in relation to tumor recurrence capacity and chemoresistance (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Furthermore, common gene variants may also predict chemoresistance and toxicity to 5-fluorouracil (5-FU) and/or oxaliplatin as recently shown for the thymidylate synthetase, 5 methyltetrahydrofolate-homocysteine methyltransferase reductase, multidrug resistance protein 2, dihydropyrimidine dehydrogenase, and the X-ray repair cross-complementing protein 1 genes (30)(31)(32)(33)(34)(35).…”