IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas.
OBJECTIVE
To establish the frequency of IDH1 mutations in glioblastomas at a population level, and to assess whether they allow reliable discrimination between primary (de novo) glioblastomas and secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma.


METHODS
We screened glioblastomas from a population-based study for IDH1 mutations and correlated them with clinical data and other genetic alterations.


RESULTS
IDH1 mutations were detected in 36 of 407 glioblastomas (8.8%). Glioblastoma patients with IDH1 mutations were younger (mean, 47.9 years) than those with EGFR amplification (60.9 years) and were associated with significantly longer survival (mean, 27.1 versus 11.3 months; P < 0.0001). IDH1 mutations were frequent in glioblastomas diagnosed as secondary (22 of 30; 73%), but rare in primary glioblastomas (14 of 377; 3.7%: P < 0.0001). IDH1 mutations as genetic marker of secondary glioblastoma corresponded to the respective clinical diagnosis in 95% of cases. Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary glioblastomas, suggesting that they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified as primary. Conversely, glioblastomas without IDH1 mutations clinically diagnosed as secondary typically developed from anaplastic rather than low-grade gliomas, suggesting that at least some were actually primary glioblastomas, that may have been misclassified, possibly due to histologic sampling error.


CONCLUSIONS
IDH1 mutations are a strong predictor of a more favorable prognosis and a highly selective molecular marker of secondary glioblastomas that complements clinical criteria for distinguishing them from primary glioblastomas.
Nobusawa
Sumihito
S
International Agency for Research on Cancer, Lyon, France.
Watanabe
Takuya
T
Kleihues
Paul
P
Ohgaki
Hiroko
H
D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000175:diagnosis* / Q000235:genetics / Q000556:secondary*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009423:Nervous System Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D016019:Survival Analysis
D014408:Biomarkers, Tumor; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human