Originally published as JCO Early Release 10.1200/JCO.2009.21.9832 on July 27 2009

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Isocitrate Dehydrogenase 1 Codon 132 Mutation Is an Important Prognostic Biomarker in Gliomas

From the L'Institut National de la Santé et de la Recherche Médicale, U711, Biologie des Interactions Neurones&Glie; Assistance Publique–Hôpitaux de Paris, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie Mazarin and Laboratoire de Neuropathologie R. Escourolle; and Université Pierre et Marie Curie, Faculté de Médecine, Paris, France.

Corresponding author: Marc Sanson, MD, PhD, L'Institut National de la Santé et de la Recherche Médicale U711, Fédération de Neurologie Mazarin, Groupe Hospitalier Pitié-Salpêtrière, 75651, Paris cedex 13, France; e-mail: marc.sanson{at}psl.ap-hop-paris.fr.

Purpose Unexpected mutations affecting the isocitrate dehydrogenase (IDH1) gene at codon 132 have been found in 12% of glioblastomas.

Patients and Methods IDH1 codon 132 sequencing was performed in a series of 404 patients with glioma (100 grade 2, 121 grade 3, and 183 grade 4 gliomas) and correlated with histology, genomic profile, methylguanyl methyltransferase (MGMT) promoter methylation status, and outcome.

Results A total of 155 codon 132 mutations were found, of which 131 were Arg132His (88.5%). The IDH1 mutation was inversely correlated with grade, affecting 77% of grade 2, 55% of grade 3, and 6% of grade 4 gliomas (P < 10^–15). The IDH1 mutation was tightly associated with a 1p19q codeleted genotype (P < 10^–14) and an MGMT methylated status (P < .001) but mutually exclusive with EGFR amplification (P < 10^–15) and loss of chromosome 10 (P < 10^–15). The presence (v absence) of IDH1 mutation was associated with a better outcome in grade 2 (150.9 v 60.1 months, respectively; P = .01), grade 3 (81.1 v 19.4 months, respectively; P < .001), and grade 4 gliomas (27.4 v 14 months, respectively; P < .01). After adjustment for grade, age, MGMT status, genomic profile, and treatment, multivariate analysis confirmed that IDH1 mutation was an independent favorable prognostic marker (hazard ratio = 0.297; 95% CI, 0.157 to 0.564, P = .00021).

Conclusion This study indicates that IDH1 codon 132 mutation is closely linked to the genomic profile of the tumor and constitutes an important prognostic marker in grade 2 to 4 gliomas.

Supported by Grant No. PL 046 from the Institut National du Cancer and the Ligue Nationale Contre le Cancer.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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