Prognostic impact of molecular markers in a series of 220 primary glioblastomas.
BACKGROUND
In contrast to oligodendrogliomas, molecular predictors of prognosis have not been consistently found in glioblastomas. However, genetic studies show that glioblastomas consist of several genetic subtypes and raise the possibility that molecular alterations could be predictive of survival.


METHODS
A search for loss of heterozygosity (LOH) on chromosome 1p, 9p, 10q, 19q, EGFR (epidermal growth factor receptor), CDK4, and MDM2 (mouse double minute) amplifications, CDKN2A (INK4A/ARF) homozygous deletions, p53 expression, was performed in a series of 220 primary glioblastomas. The molecular alterations were then correlated with each other to identify distinct molecular pathways and with clinical parameters and the course of the disease to identify prognostic markers.


RESULTS
Nonrandom associations were found between EGFR amplification and LOH10q, LOH9p, and INK4A/ARF deletion, LOH1p and LOH19q, and MDM2 and CDK4 amplification, whereas mutual exclusions were found between p53 expression and EGFR amplification, LOH 9p/INK4A/ARF homozygous deletion, and MDM2 and CDK4 amplification. Age (P = 4.10(-5)) and performance status (P = .003) were the main predictors of outcome. In contrast, molecular markers were of limited impact: MDM2 amplification correlated with poor outcome on both univariate and multivariate analysis (P = .01) and EGFR amplification with good prognosis on multivariate analysis (P = .02).


CONCLUSIONS
Despite their limited prognostic impact, the genetic markers investigated here outline distinct molecular pathways involved in glioblastoma tumorigenesis and warrant broader molecular screening.
Mazarin Neurology Service and INSERM U711, Biology of Neuronal and Glial Interactions, Paris, France.
Caroline
C
Houillier
Julie
J
Lejeune
Alexandra
A
Benouaich-Amiel
Florence
F
Laigle-Donadey
Emmanuelle
E
Criniere
Karima
K
Mokhtari
Joelle
J
Thillet
Jean-Yves
JY
Delattre
Khe
K
Hoang-Xuan
Marc
M
Sanson
D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018773:Genes, erbB-1 / Q000235:genetics*; D005819:Genetic Markers; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011336:Probability; D011379:Prognosis; D016016:Proportional Hazards Models; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D012042:Registries; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D016019:Survival Analysis
D005819:Genetic Markers; D051736:Proto-Oncogene Proteins c-mdm2