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Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis

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Abstract

The phenotypic heterogeneity of low-grade gliomas (LGGs) is still inconsistently explained by known molecular abnormalities in patients treated according to the present standards of care. IDH1 codon 132 and IDH2 codon 172 sequencing was performed in a series of 47 LGGs and correlated with clinical presentation, MR imaging characteristics, genomic profile and outcome. A total of 38 IDH1 mutations at codon 132 and 2 IDH2 mutations at codon 172 were found, including 35 R132H (87.5%), 2 R132C (5.0%), 1 R132S (2.5%) and 2 R172 M (5%). The IDH mutations were significantly associated with 1p19q deleted genotype (P = 0.031) and p53 expression (P = 0.014). The presence (vs. absence) of IDH mutations was associated with a better outcome (5-year survival rate, 93% vs. 51%, respectively, P = 0.000001). After adjustment for age, tumor location and size, radiologic infiltration pattern and extent of surgery, multivariate analysis confirmed that IDH mutations was an independent favorable prognostic factor (hazard ratio = 40.9; 95% CI, 2.89–578.49, P = 0.006). Furthermore, we showed that patients with IDH-nonmutated tumors were significantly older (P = 0.020) and that these tumors involved significantly more frequently the insula (P = 0.004), were larger in size (>6 cm, P = 0.047), displayed an infiltrative pattern on MRI (P = 0.007) and were all p53 negative with no 1p19q deletion (P < 10−6). The absence of IDH mutations in LGGs identifies a novel entity of LGGs with distinctive location, infiltrative behavior, specific molecular alterations, and dismal outcome. These findings could significantly modify the LGG classification and may represent a new tool to guide patient-tailored therapy.

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Acknowledgments

We are grateful to Drs C. Bouvier, C. Fernandez, C. Courdy and A. Maues de Paula for their help in tumor handling and pathological diagnoses, to C. Boucard for managing clinical informations regarding the patients, to Dr S. Romain for frozen tissue management, to D. Intagliata, L. Scapuccini, F. Frassinetti, N. Baeza, S. Tong, A. Durand, S. Gilles, M. Molina and C. Schiano for technical assistance.

This work was supported by the Canceropole PACA institutional Grants, by INCa (Institut National du Cancer) grants RS019 and Gliother, by the GEFLUC (groupement des enterprises françaises dans la lutte contre le cancer) and by ARTC-Sud by (Association pour la Recherche sur les Tumeurs Cérébrales).

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Authors and Affiliations

  1. Service de Neurochirurgie, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, 13000, France

    Philippe Metellus

  2. INSERM, UMR 911, Marseille, 13000, France

    Philippe Metellus, Carole Colin,  L’Houcine Ouafik, Olivier Chinot & Dominique Figarella-Branger

  3. Faculté de Médecine, Aix-Marseille Université, Marseille, 13000, France

    Philippe Metellus, Carole Colin, Anne Barlier,  L’Houcine Ouafik, Olivier Chinot & Dominique Figarella-Branger

  4. Service d’Anatomie Pathologique et de Neuropathologie, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, 13000, France

    Bema Coulibaly, Andre Maues de Paula, Alexandre Vasiljevic & Dominique Figarella-Branger

  5. Service Central de Biophysique et Médecine nucléaire, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, 13000, France

    David Taieb

  6. CNRS, UMR 6544, Marseille, 13000, France

    Anne Barlier

  7. Université Pierre et Marie Curie, Paris 6, CRICM, UMR-S975, Paris, 75013, France

    Blandine Boisselier, Karima Mokhtari & Xiao Wei Wang

  8. INSERM, U 975, Paris, 75013, France

    Blandine Boisselier, Karima Mokhtari & Xiao Wei Wang

  9. CNRS, UMR 7225, Paris, 75013, France

    Blandine Boisselier, Karima Mokhtari & Xiao Wei Wang

  10. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Unité d’Aide méthodologique à la Recherche Clinique et Epidémiologique, DRRC, Marseille, 13000, France

    Anderson Loundou

  11. Service de Neuroradiologie, Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Marseille, 13000, France

    Frederique Chapon & Sandrine Pineau

  12. Assistance Publique-Hôpitaux de Marseille, Hôpital de la Timone, Unité de Neurooncologie, Marseille, 13000, France

    Olivier Chinot

  13. Service de Neurochirurgie, Hôpital de la Timone, 264, rue Saint-Pierre, Marseille Cedex, 13385, France

    Philippe Metellus

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  1. Philippe Metellus
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Correspondence to Philippe Metellus.

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Metellus, P., Coulibaly, B., Colin, C. et al. Absence of IDH mutation identifies a novel radiologic and molecular subtype of WHO grade II gliomas with dismal prognosis. Acta Neuropathol 120, 719–729 (2010). https://doi.org/10.1007/s00401-010-0777-8

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