Association between SNPs in Wnt signaling pathway genes and ovarian cancer risk in Northern Chinese population

Objective: Wnt signaling pathway is important for tumorigenesis, due to its regulation of many critical biological processes, while the association between SNPs in Wnt pathway genes and ovarian cancer risk has not been established in Chinese, the authors performed a large case control study to analyze this association. Materials and Methods: A case control study was designed including 732 ovarian cancer cases and 765 controls. A total of six SNPs in five core genes in Wnt pathway were genotyped in all the samples. Logistic regression analysis was performed to evaluate the association between SNPs and ovarian cancer risk, odds ratios (ORs), and 95% confidence intervals (CIs) were estimated. Results: In the univariate analysis, among the six SNPs, the authors found two SNPs significantly associated with ovarian cancer risk. One is SNP rs4135385 in β-catenin gene, compared with AA genotype, GG genotype was associated with a significant lower risk of ovarian cancer, OR=0.62; 95% CI (0.45, 0.87). The other is SNP rs6485350 in DKK3 gene, compared with GG genotype, AA genotype was associated with a significant lower risk of ovarian cancer, OR=0.73; 95% CI (0.55, 0.98). In the multivariate analysis adjusting for common demographic variable, the authors found SNP rs4135385 in β-catenin gene significantly associated with ovarian cancer risk, Compared with AA genotype, GG genotype was associated with a significant lower risk of ovarian cancer, OR=0.57; 95% CI (0.40, 0.79), p = 0.006. After Bonferroni’s correction for six SNPs, this SNP rs4135385 was still significantly associated with ovarian cancer risk. Conclusion: In this case control study, the authors found significant association between SNP in β-catenin gene and ovarian cancer risk in Northern Chinese and further studies are warranted to validate their finding and investigate the mechanism for the association.

Ovarian cancer; Case control study; Wnt pathway; β-catenin.

[1] Ferlay J., Shin H.R., Bray F., Forman D., Mathers C., Parkin D.M.: “Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008”. Int. J. Cancer, 2010, 127, 2893.

[2] Sueblinvong T., Carney M.E.: “Current understanding of risk factors for ovarian cancer”. Curr. Treat. Options Oncol., 2009, 10, 67.

[3] Lancaster J.M., Powell C.B., Kauff N.D., Cass I., Chen L.M., Lu K.H., et al.: “Society of Gynecologic Oncologists Education Committee statement on risk assessment for inherited gynecologic cancer predispositions”. Gynecol. Oncol., 2007, 107, 159.

[4] Doherty J.A., Rossing M.A., Cushing-Haugen K.L., Chen C., Van Den Berg D.J., Wu A.H., et al.: “ESR1/SYNE1 polymorphism and invasive epithelial ovarian cancer risk: an Ovarian Cancer Association Consortium study”. Cancer Epidemiol. Biomarkers Prev., 2010, 19, 245.

[5] Ratner E., Lu L., Boeke M., Barnett R., Nallur S., Chin L.J., et al.: “A KRAS-variant in ovarian cancer acts as a genetic marker of cancer risk”. Cancer Res., 2010, 70, 6509.

[6] Braem M.G., Schouten L.J., Peeters P.H., van den Brandt P.A., Onland-Moret N.C.: “Genetic susceptibility to sporadic ovarian cancer: a systematic review”. Biochim. Biophys. Acta, 2011, 1816, 132.

[7] Notaridou M., Quaye L., Dafou D., Jones C., Song H., Hogdall E., et al.: “Common alleles in candidate susceptibility genes associated with risk and development of epithelial ovarian cancer”. Int. J. Cancer, 2011, 128, 2063.

[8] Cunningham J.M., Vierkant R.A., Sellers T.A., Phelan C., Rider D.N., Liebow M., et al.: “Cell cycle genes and ovarian cancer susceptibility: a tagSNP analysis”. Br. J. Cancer, 2009, 101, 1461.

[9] Lurie G., Wilkens L.R., Thompson P.J., Carney M.E., Palmieri R.T., Pharoah P.D., et al.: “Vitamin D receptor rs2228570 polymorphism and invasive ovarian carcinoma risk: pooled analysis in five studies within the Ovarian Cancer Association Consortium”. Int. J. Cancer, 2011, 128, 936.

[10] Phelan C.M., Tsai Y.Y., Goode E.L., Vierkant R.A., Fridley B.L., Beesley J., et al.: “Polymorphism in the GALNT1 gene and epithelial ovarian cancer in non-Hispanic white women: the Ovarian Cancer Association Consortium”. Cancer Epidemiol. Biomarkers Prev., 2010, 19, 600.

[11] Schildkraut J.M., Iversen E.S., Wilson M.A., Clyde M.A., Moorman P.G., Palmieri R.T., et al.: “Association between DNA damage response and repair genes and risk of invasive serous ovarian cancer”. PLoS One, 2010, 5, e10061.

[12] Jeays-Ward K., Hoyle C., Brennan J., Dandonneau M., Alldus G., Capel B., et al.: “Endothelial and steroidogenic cell migration are regulated by WNT4 in the developing mammalian gonad”. Development, 2003, 130, 3663.

[13] Yao H.H., Matzuk M.M., Jorgez C.J., Menke D.B., Page D.C., Swain A., et al.: “Follistatin operates downstream of Wnt4 in mammalian ovary organogenesis”. Dev. Dyn., 2004, 230, 210.

[14] Ricken A., Lochhead P., Kontogiannea M., Farookhi R.: “Wnt signaling in the ovary: identification and compartmentalized expression of wnt-2, wnt-2b, and frizzled-4 mRNAs”. Endocrinology, 2002, 143, 2741.

[15] Vogelstein B., Fearon E.R., Hamilton S.R., Kern S.E., Preisinger A.C., Leppert M., et al.: “Genetic alterations during colorectal-tumor development”. N. Engl. J. Med., 1988, 319, 525.

[16] Sparks A.B., Morin P.J., Vogelstein B., Kinzler K.W.: “Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer”. Cancer Res., 1998, 58, 1130.

[17] Palacios J., Gamallo C.: “Mutations in the beta-catenin gene (CTNNB1) in endometrioid ovarian carcinomas”. Cancer Res., 1998, 58, 1344.

[18] Gamallo C., Palacios J., Moreno G., Calvo D.M.J., Suarez A, Armas A.: “Beta-catenin expression pattern in stage I and II ovarian carcinomas: relationship with beta-catenin gene mutations, clinicopathological features, and clinical outcome”. Am. J. Pathol., 1999, 155, 527.

[19] Sagae S., Kobayashi K., Nishioka Y., Sugimura M., Ishioka S., Nagata M., et al.: “Mutational analysis of beta-catenin gene in Japanese ovarian carcinomas: frequent mutations in endometrioid carcinomas”. Jpn. J. Cancer Res., 1999, 90, 510.

[20] Habano W., Sugai T., Yoshida T., Nakamura S.: “Mitochondrial gene mutation, but not large-scale deletion, is a feature of colorectal carcinomas with mitochondrial microsatellite instability”. Int. J. Cancer, 1999, 83, 625.

[21] Saegusa M., Okayasu I.: “Frequent nuclear beta-catenin accumulation and associated mutations in endometrioid-type endometrial and ovarian carcinomas with squamous differentiation”. J. Pathol., 2001, 194, 59.

[22] Wu R., Zhai Y., Fearon E.R., Cho K.R.: “Diverse mechanisms of beta-catenin deregulation in ovarian endometrioid adenocarcinomas”. Cancer Res., 2001, 61, 8247.

[23] Wang Y., Hewitt S.M., Liu S., Zhou X., Zhu H., Zhou C., et al.: “Tissue microarray analysis of human FRAT1 expression and its correlation with the subcellular localisation of beta-catenin in ovarian tumours”. Br. J. Cancer, 2006, 94, 686.

[24] Karbova E., Davidson B., Metodiev K., Trope C.G., Nesland J.M.: “Adenomatous polyposis coli (APC) protein expression in primary and metastatic serous ovarian carcinoma”. Int. J. Surg. Pathol., 2002, 10, 175.

[25] Lee C.M., Shvartsman H., Deavers M.T., Wang S.C., Xia W., Schmandt R., et al.: “Beta-catenin nuclear localization is associated with grade in ovarian serous carcinoma”. Gynecol. Oncol., 2003, 88, 363.

[26] Gatcliffe T.A., Monk B.J., Planutis K., Holcombe R.F.: “Wnt signaling in ovarian tumorigenesis”. Int. J. Gynecol. Cancer, 2008, 18, 954. [27] Yo Y.T., Lin Y.W., Wang Y.C., Balch C., Huang R.L., Chan M.W., et al.: “Growth inhibition of ovarian tumor-initiating cells by niclosamide”. Mol. Cancer Ther., 2012, 11, 1703.