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[Cancer Research 64, 6892-6899, October 1, 2004]
© 2004 American Association for Cancer Research


Regular Articles

Genetic Pathways to Glioblastoma

A Population-Based Study

Hiroko Ohgaki1, Pierre Dessen1, Benjamin Jourde1, Sonja Horstmann1, Tomofumi Nishikawa1, Pier-Luigi Di Patre1, Christoph Burkhard1, Danielle Schüler2, Nicole M. Probst-Hensch2, Paulo César Maiorka1, Nathalie Baeza1, Paola Pisani1, Yasuhiro Yonekawa4, M. Gazi Yasargil3, Urs M. Lütolf4 and Paul Kleihues4

1 International Agency for Research on Cancer, Lyon, France; 2 Cancer Registry, Canton of Zurich, Zurich, Switzerland; 3 Department of Neurosurgery, College of Medicine, Little Rock, Arkansas; and 4 Departments of Neurosurgery, Radiology, and Pathology, University Hospital Zurich, Zurich, Switzerland

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%), p16INK4a 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.




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