title: Expression and prognostic value of the WEE1 kinase in gliomas.
abstract: High-grade gliomas have an aggressive clinical course and new clinical biomarkers and therapeutic targets are highly needed. WEE1 is a regulator of the G2 checkpoint in glioblastoma (GBM) cells. Inhibition of this kinase has, in experimental glioma studies, been suggested to enhance sensitivity to irradiation and temozolomide. However, expression level and prognostic potential of WEE1 protein in gliomas remain uninvestigated. In this study, glioma samples from 235 patients across all four WHO grades were analyzed by immunohistochemistry. Using image analysis, we calculated the area fraction of WEE1 positive nuclei. We found that WEE1 protein was localized in tumor cell nuclei and expressed in all glioma types and grades. Although WEE1 protein levels are higher in GBMs (mean 24.5%) relative to grade III (mean 14,0%, p < 0.05) and grade II (mean 6.8%, p < 0.001) gliomas, high WEE1 protein was associated with better survival in GBMs (p = 0.002). This was confirmed in multivariate analysis (HR 0.60, p = 0.003) even when adjusted for MGMT status (HR 0.60, p = 0.005). In conclusion, we report a nuclear expression of WEE1 protein in all glioma grades and types. The WEE1 positive nuclear area was correlated with malignancy grade but it was inversely associated with prognosis in GBM. Although WEE1 is a frequently occurring protein and has been proposed as a novel target in GBM, the role of WEE1 in glioma patient survival appears to be connected to the MGMT status and is more complex than previously anticipated.
authors.affiliation: Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark.
authors.forename: Darija
authors.initials: D
authors.lastname: Music
authors.affiliation: Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark.|Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark.
authors.forename: Rikke Hedegaard
authors.initials: RH
authors.lastname: Dahlrot
authors.affiliation: Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark.|Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, Odense C, Denmark.
authors.forename: Simon Kjær
authors.initials: SK
authors.lastname: Hermansen
authors.affiliation: Department of Epidemiology, Biostatistics and Biodemography, Institute of Public Health, University of Southern Denmark, J.B. Winsløws Vej 9, Odense C, Denmark.
authors.forename: Jacob
authors.initials: J
authors.lastname: Hjelmborg
authors.affiliation: Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark.
authors.forename: Karin
authors.initials: K
authors.lastname: de Stricker
authors.affiliation: Department of Oncology, Odense University Hospital, Sdr. Boulevard 29, Odense C, Denmark.|Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, Odense C, Denmark.
authors.forename: Steinbjørn
authors.initials: S
authors.lastname: Hansen
authors.affiliation: Department of Pathology, Odense University Hospital, J. B. Winsløws Vej 15, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk.|Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19, Odense C, Denmark. bjarne.winther.kristensen@rsyd.dk.
authors.forename: Bjarne Winther
authors.initials: BW
authors.lastname: Kristensen
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D018797:Cell Cycle Proteins / Q000378:metabolism*; D015254:DNA Modification Methylases / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000378:metabolism*; D005500:Follow-Up Studies; D005910:Glioma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007124:Immunoenzyme Techniques; D060787:Neoplasm Grading; D009687:Nuclear Proteins / Q000378:metabolism*; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D012189:Retrospective Studies; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D045643:DNA Repair Enzymes
keywords: Biomarker; Glioblastoma; Glioma; Immunohistochemistry; Prognosis; WEE1