Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients.
OBJECTIVE
Despite multimodal aggressive treatment glioblastoma patients still face a rather poor prognosis. Recent data indicate that certain molecular markers, in particular MGMT promoter hypermethylation, are associated with response to alkylating chemotherapy and longer survival. The clinical significance of other glioblastoma-associated molecular aberrations and their relationship to MGMT promoter hypermethylation is still poorly understood.


METHODS
We conducted a translational study involving 67 newly diagnosed glioblastoma patients treated at our institution from 1998 to 2004. All patients were treated by open resection, followed by radiotherapy and adjuvant temozolomide chemotherapy. The tumors were investigated for MGMT promoter methylation, mRNA and protein expression, as well as presence of MGMT sequence polymorphisms. In addition, we screened for genetic aberrations of the EGFR, TP53, CDK4, MDM2, and PDGFRA genes as well as allelic losses on chromosomal arms 1p, 10q, and 19q.


RESULTS
Correlation of molecular findings with clinical data revealed significantly longer time to progression after onset of chemotherapy and longer overall survival of patients with MGMT-hypermethylated tumors. In contrast, MGMT protein expression, MGMT polymorphisms, and aberrations in any of the other genes and chromosomes were not significantly linked to patient outcome. Multivariate analysis identified MGMT promoter hypermethylation and near-complete tumor resection as the most important parameters associated with better prognosis.


CONCLUSIONS
Our study provides novel insights into the significance of molecular and clinical markers in predicting the prognosis of glioblastoma patients, which may improve stratification of patients into distinct prognostic subgroups.
Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
Jörg
J
Felsberg
Marion
M
Rapp
Simon
S
Loeser
Rolf
R
Fimmers
Walter
W
Stummer
Matthias
M
Goeppert
Hans-Jacob
HJ
Steiger
Britta
B
Friedensdorf
Guido
G
Reifenberger
Michael C
MC
Sabel
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D001932:Brain Neoplasms / Q000235:genetics* / Q000601:surgery / Q000628:therapy; D002878:Chromosomes, Human, Pair 1; D002879:Chromosomes, Human, Pair 10; D002888:Chromosomes, Human, Pair 19; D003131:Combined Modality Therapy; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000032:analysis* / Q000235:genetics; D045643:DNA Repair Enzymes / Q000032:analysis* / Q000235:genetics; D005260:Female; D005909:Glioblastoma / Q000235:genetics* / Q000601:surgery / Q000628:therapy*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000032:analysis* / Q000235:genetics
D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes