title: Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma.
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 (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.
  
  
  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.
authors.affiliation: Department of Neurosurgery, Nordstadt Hospital Hannover, Hannover, Germany.
authors.forename: Salveena
authors.initials: S
authors.lastname: Schiffgens
authors.affiliation: Department of Pathology, Nordstadt Hospital Hannover, Hannover, Germany.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Wilkens
authors.affiliation: Department of Medical Oncology, Bellaria Hospital, AUSL-IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Alba A
authors.initials: AA
authors.lastname: Brandes
authors.affiliation: Department of Pathology, Nordstadt Hospital Hannover, Hannover, Germany.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Meier
authors.affiliation: Department of Medical Oncology, Bellaria Hospital, AUSL-IRCCS Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Franceschi
authors.affiliation: Department of Neurosciences, Statistics and Informatics Unit, University Hospital Padova, Padua, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Ermani
authors.affiliation: Department of Neuropathology, Institute of Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hartmann
authors.affiliation: Department of Neurosurgery, Nordstadt Hospital Hannover, Hannover, Germany.
authors.forename: Ibrahim Erol
authors.initials: IE
authors.lastname: Sandalcioglu
authors.affiliation: Department of Neurosurgery, Nordstadt Hospital Hannover, Hannover, Germany.
authors.forename: Claudia A
authors.initials: CA
authors.lastname: Dumitru
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000401:mortality / Q000473:pathology*; D015254:DNA Modification Methylases / Q000032:analysis* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000032:analysis* / Q000235:genetics; D005260:Female; D051157:Frizzled Receptors / Q000032:analysis*; D005909:Glioblastoma / Q000401:mortality / Q000473:pathology*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012727:Sex Characteristics; D046888:Tissue Array Analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C115810:FZD7 protein, human; D051157:Frizzled Receptors; D025521:Tumor Suppressor Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: Frizzled-7; IDH1; MGMT; glioblastoma; sex-specific biomarkers