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cMYC expression in infiltrating gliomas: associations with IDH1 mutations, clinicopathologic features and outcome

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Abstract

Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. cMYC is an oncogene also implicated in aberrant metabolism, but its prognostic impact remains unclear. Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1. We evaluated nuclear cMYC protein levels and IDH1 (R132H) by immunohistochemistry in patients with oligodendroglioma/oligoastrocytomas (n = 20), astrocytomas (grade II) (n = 19), anaplastic astrocytomas (n = 21) or glioblastomas (n = 111). Of 158 tumors with sufficient tissue, 110 (70 %) showed nuclear cMYC immunopositivity—most frequent (95 %, χ2 p = 0.0248) and intense (mean 1.33, ANOVA p = 0.0179) in anaplastic astrocytomas versus glioblastomas (63 %) or low grade gliomas (74 %). cMYC expression associated with younger age as well as p53 immunopositivity (OR = 3.6, p = 0.0332) and mutant IDH1 (R132H) (OR = 7.4, p = 0.06) among malignant gliomas in our cohort. Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression. Both IDH1 (R132H) and cMYC protein expression were associated with improved overall survival by univariate analysis. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas.

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Acknowledgments

Grant funding provided in part by the National Institute of Neurological Disorders and Stroke (NINDS) Research Education Program for Residents and Fellows in Neurology and Neurosurgery (2009–10)—Primary Investigator Argye Hillis, MD MS, Johns Hopkins Hospital, Baltimore, MD [NINDS 5R25NS065729-02] (YO); Children’s Cancer Foundation, Inc. (CGE,FJR), 5R01NS055089 (CGE), and James S. McDonnell Foundation (CGE). Jessica Hicks performed all cMYC immunohistochemistry on glioma specimens. The authors also thank the Mayo Clinic cytogenetic shared resource for technical assistance.

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The authors have no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yazmin Odia

  2. Division of Neuropathology, Department of Pathology, Johns Hopkins Hospital, The Johns Hopkins University School of Medicine, Sheikh Zayed Tower, Room M2101, 1800 Orleans Street, Baltimore, MD, 21231, USA

    Brent A. Orr, W. Robert Bell, Charles G. Eberhart & Fausto J. Rodriguez

  3. The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Charles G. Eberhart & Fausto J. Rodriguez

  4. Neuro-Oncology Branch, National Cancer Institute, Bethesda, MD, USA

    Yazmin Odia

  5. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Brent A. Orr

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Odia, Y., Orr, B.A., Robert Bell, W. et al. cMYC expression in infiltrating gliomas: associations with IDH1 mutations, clinicopathologic features and outcome. J Neurooncol 115, 249–259 (2013). https://doi.org/10.1007/s11060-013-1221-4

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