Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma

// Salveena Schiffgens 1 , Ludwig Wilkens 2 , Alba A. Brandes 3 , Tatiana Meier 2 , Enrico Franceschi 3 , Mario Ermani 4 , Christian Hartmann 5 , Ibrahim Erol Sandalcioglu 1 , Claudia A. Dumitru 1 1 Department of Neurosurgery, Nordstadt Hospital Hannover, Hannover, Germany 2 Department of Pathology, Nordstadt Hospital Hannover, Hannover, Germany 3 Department of Medical Oncology, Bellaria Hospital, AUSL-IRCCS Institute of Neurological Sciences, Bologna, Italy 4 Department of Neurosciences, Statistics and Informatics Unit, University Hospital Padova, Padua, Italy 5 Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany Correspondence to: Claudia A. Dumitru, email: claudia.dumitru@krh.eu Keywords: Frizzled-7, MGMT, IDH1, sex-specific biomarkers, glioblastoma Received: February 12, 2016     Accepted: June 30, 2016     Published: July 07, 2016 ABSTRACT Background : The Wnt receptor Frizzled-7 (FZD7) promotes tumor progression and can be currently targeted by monoclonal antibody therapy. Here, we determined the prognostic value of FZD7 for the overall survival of glioblastoma (GBM) patients, both as individual marker and taken in combination with the previously-described markers MGMT and IDH1. Additionally, we tested whether these markers (alone or in combination) exhibited sex-specific differences. Results: High levels of FZD7 (FZD7 high ) associated with shorter survival in GBM patients; however, FZD7 high was a significant predictor of poor survival only in male patients. Mutation of IDH1 significantly associated with longer survival in male but not female patients. Methylated MGMT promoter significantly associated with longer survival only in female patients. Combination of FZD7 with MGMT enhanced the prognostic accuracy and abrogated the sex differences observed upon single marker analysis. Combination of FZD7 with IDH1 was a significant predictor of survival in male GBM patients only. Materials and Methods: Three independent cohorts of patients with primary GBM (n=120, n=108 and n=105, respectively) were included in this study. FZD7 and IDH1 were assessed by immunohistochemistry in tissue microarrays. MGMT promoter methylation was determined by methylation-specific polymerase chain reaction. Survival analysis was performed by Kaplan-Meier estimate, log-rank test and Cox proportional hazard regression. Conclusions: Our study identifies novel individual and combination markers with prognostic and, possibly, therapeutic relevance in GBM. Furthermore, our findings substantiate the importance of sexual dimorphism in this type of cancer.