title: Anti-O6-methylguanine-methyltransferase (MGMT) immunohistochemistry in glioblastoma multiforme: observer variability and lack of association with patient survival impede its use as clinical biomarker.
abstract: Silencing of O6-methylguanine-DNA methyltransferase (MGMT) protein expression because of MGMT gene promoter hypermethylation is considered to be associated with postoperative chemoradiotherapy benefits in glioblastoma multiforme (GBM) patients. The objective of this study was to clarify the usability of MGMT immunohistochemistry (IHC) as a clinical biomarker. We immunostained a tissue microarray containing biopsy samples of 164 GBM patients from the European Organization for Research and Treatment of Cancer and the National Cancer Institute of Canada (EORTC/NCIC) trial 26981/22981 using two commercial anti-MGMT antibodies (clones MT3.1 and MT23.2). Immunostaining results were semiquantitatively evaluated by four observers from three neuropathological laboratories using a predefined algorithm. We analyzed (i) inter- and intraobserver agreement on MGMT expression (kappa statistics); (ii) correlation of MGMT expression with MGMT promoter methylation status (kappa statistics); and (iii) correlation of MGMT expression with patient outcome (log-rank test). Interobserver agreement on MGMT expression varied from slight to almost perfect, whereas intraobserver agreement ranged from substantial to almost perfect. MGMT expression showed poor to moderate correlation with MGMT promoter methylation status. We found no significant association of MGMT expression with patient outcome. In our hands, observer variability as well as lack of association with the MGMT promoter methylation status and patient survival impeded the use of anti-MGMT immunohistochemistry as a clinical biomarker for routine diagnostic purposes.
authors.affiliation: Department of Internal Medicine 1, Medial University of Vienna, Vienna, Austria.
authors.forename: Matthias
authors.initials: M
authors.lastname: Preusser
authors.forename: Robert
authors.initials: R
authors.lastname: Charles Janzer
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Hamou
authors.forename: Annie-Claire
authors.initials: AC
authors.lastname: Diserens
authors.forename: Roger
authors.initials: R
authors.lastname: Stupp
authors.forename: Thierry
authors.initials: T
authors.lastname: Gorlia
authors.forename: Christine
authors.initials: C
authors.lastname: Marosi
authors.forename: Harald
authors.initials: H
authors.lastname: Heinzl
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Hainfellner
authors.forename: Monika
authors.initials: M
authors.lastname: Hegi
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies; D000918:Antibody Specificity; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000201:enzymology* / Q000503:physiopathology; D015331:Cohort Studies; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D003937:Diagnosis, Differential; D005909:Glioblastoma / Q000175:diagnosis* / Q000201:enzymology* / Q000503:physiopathology; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D015588:Observer Variation; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic / Q000235:genetics; D011446:Prospective Studies; D015203:Reproducibility of Results; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D000906:Antibodies; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes