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

Salveena Schiffgens,Christian Hartmann,Enrico Franceschi,Ibrahim Erol Sandalcioglu,Claudia A. Dumitru,Mario Ermani,Alba A. Brandes,Ludwig Wilkens,Tatiana Meier

doi:10.18632/oncotarget.10465

Abstract

BackgroundThe 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.ResultsHigh levels of FZD7 (FZD7high) associated with shorter survival in GBM patients; however, FZD7high 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 MethodsThree 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.ConclusionsOur 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.

Highlights

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults with an incidence of 0.59-3.69 cases per 100,000 person life-years [1]
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

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive malignant brain tumor in adults with an incidence of 0.59-3.69 cases per 100,000 person life-years [1]. The mean age of primary and secondary GBM patients is 62 and 45 years, respectively [2]. The standard of care treatment for GBM consists of maximum safe surgical resection followed by radiotherapy plus concomitant and adjuvant chemotherapy with temozolomide [3]. Despite this aggressive therapeutic regimen, GBM patients have a very poor prognosis, with www.impactjournals.com/oncotarget only 0.05-4.7% of patients surviving 5 years past initial diagnosis [1]. 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. We tested whether these markers (alone or in combination) exhibited sex-specific differences

Objectives

Results

Conclusion