IDH1 Mutations as Molecular Signature and Predictive Factor of Secondary Glioblastomas

• DOI: 10.1158/1078-0432.ccr-09-0715
• Publication Date: 2009-09-16T03:30:26Z
• Authors: Sumihito Nobusawa; Takuya Watanabe; Paul Kleihues; Hiroko Ohgaki
• Keywords: Adult; Male; Base Sequence; Gene Expression Profiling; DNA Mutational Analysis; Nervous System Neoplasms; Astrocytoma; Middle Aged; Prognosis; Survival Analysis; Isocitrate Dehydrogenase; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Mutation; Biomarkers, Tumor; Humans; Female; Glioblastoma; Aged

Abstract Purpose: 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. Experimental Design: 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. Conclusion: 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. (Clin Cancer Res 2009;15(19):6002–7)