Genetic pathways to glioblastoma: a population-based study.
We conducted a population-based study on glioblastomas in the Canton of Zurich, Switzerland (population, 1.16 million) to determine the frequency of major genetic alterations and their effect on patient survival. Between 1980 and 1994, 715 glioblastomas were diagnosed. The incidence rate per 100,000 population/year, adjusted to the World Standard Population, was 3.32 in males and 2.24 in females. Observed survival rates were 42.4% at 6 months, 17.7% at 1 year, and 3.3% at 2 years. For all of the age groups, younger patients survived significantly longer, ranging from a median of 8.8 months (<50 years) to 1.6 months (>80 years). Loss of heterozygosity (LOH) 10q was the most frequent genetic alteration (69%), followed by EGFR amplification (34%), TP53 mutations (31%), p16(INK4a) deletion (31%), and PTEN mutations (24%). LOH 10q occurred in association with any of the other genetic alterations and was predictive of shorter survival. Primary (de novo) glioblastomas prevailed (95%), whereas secondary glioblastomas that progressed from low-grade or anaplastic gliomas were rare (5%). Secondary glioblastomas were characterized by frequent LOH 10q (63%) and TP53 mutations (65%). Of the TP53 mutations in secondary glioblastomas, 57% were in hotspot codons 248 and 273, whereas in primary glioblastomas, mutations were more equally distributed. G:C-->A:T mutations at CpG sites were more frequent in secondary than primary glioblastomas (56% versus 30%; P = 0.0208). This suggests that the acquisition of TP53 mutations in these glioblastoma subtypes occurs through different mechanisms.
Ohgaki
Hiroko
H
International Agency for Research on Cancer, Lyon, France. ohgaki@iarc.fr
Dessen
Pierre
P
Jourde
Benjamin
B
Horstmann
Sonja
S
Nishikawa
Tomofumi
T
Di Patre
Pier-Luigi
PL
Burkhard
Christoph
C
Schüler
Danielle
D
Probst-Hensch
Nicole M
NM
Maiorka
Paulo César
PC
Baeza
Nathalie
N
Pisani
Paola
P
Yonekawa
Yasuhiro
Y
Yasargil
M Gazi
MG
Lütolf
Urs M
UM
Kleihues
Paul
P
D000328:Adult; D000367:Age Factors; D000368:Aged; D001932:Brain Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D018773:Genes, erbB-1 / Q000235:genetics; D016158:Genes, p53 / Q000235:genetics; D005909:Glioblastoma / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D006801:Humans; D015994:Incidence; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D051059:PTEN Phosphohydrolase; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics; D012737:Sex Factors; D013557:Switzerland / Q000453:epidemiology; D025521:Tumor Suppressor Proteins / Q000235:genetics
D019941:Cyclin-Dependent Kinase Inhibitor p16; D025521:Tumor Suppressor Proteins; D010744:Phosphoric Monoester Hydrolases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human