Geburtshilfe Frauenheilkd 2006; 66 - PO_O_01_11
DOI: 10.1055/s-2006-952357

Wnt-Signaling genes and their potential as tumor markers for epithelial ovarian cancer

VA Heinzelmann-Schwarz 1, JP Scurry 2, RL Sutherland 3, NF Hacker 4, DA Fink 1, PM O'Brien 3
  • 1Universitätsspital Zürich, Klinik für Gynäkologie, Zürich, Schweiz
  • 2South Eastern Area Laboratory Service, Prince of Wales Hospital, Sydney, Australia
  • 3Garvan Institute of Medical Research, Cancer Research Program, Sydney, Australia
  • 4Royal Hospital for Women, Gynaecological Cancer Centre, Sydney, Australia

Introduction:

The Wnt/beta-catenin-signaling pathway has been increasingly implicated in a variety of cancers, including epithelial ovarian cancer (EOC). However, the nature of Wnt-signaling defects other than beta-catenin are unknown. The frizzled protein sFRP4 has putative inhibitory activity of the Wnt-signaling cascade through binding and sequestering Wnt ligands. Fibroblast growth factors (FGF) have been described to interact with beta-catenin, TGF-beta and steroid receptors. FGF9 has recently been proposed to be a key downstream target contributing to the cancer phenotype of endometrioid EOC carrying Wnt-pathway defects.

Material and Methods: Both sFRP4 and FGF9 were identified as upregulated genes in EOC using microarray technology. Furthermore, FGF9 was the top candidate in a meta-analysis performed within 3 Affymetrix microarray studies. Validation of the data by immunohistochemistry was performed on a cohort of 121 EOC, 34 borderline tumours and 12 normal ovaries. Secreted expression of both genes was tested in an ELISA experiment.

Results: Both sFRP4 and FGF9 expressed epithelial-specific immunoreactivity. In serous ovarian cancer (SOC) 76% of tumors expressed membranous sFRP4 and 96% cytoplasmatic FGF9. There was only minor expression of sFRP4, and no expression of FGF9 in normal ovarian surface epithelium (sFRP4 p=0.022; FGF9 p<0.0001). High expression of FGF9 could be found in all subtypes of EOC. Kaplan-Meier analysis revealed that EOC patients with tumors expressing sFRP4 had earlier relapse in a univariate analysis (p=0.0004), and analysed with residual disease (p=0.036) and tumor stage (p=0.0031) in a multivariate Cox proportional hazards model (p=0.034). Preliminary data using ELISA revealed expression of both genes in EOC patients.

Conclusion: Both sFRP4 and FGF9 are highly expressed in EOC and have potential as tumor markers due to their secreted function. SFRP4 is further a predictor of earlier relapse in EOC patients.