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

• Published in: Journal of neuro-oncology 2013-11, Vol.115 (2), p.249-259
• Main Authors: Odia, Yazmin, Orr, Brent A., Robert Bell, W., Eberhart, Charles G., Rodriguez, Fausto J.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Clinical Study; Cohort Studies; DNA Copy Number Variations; Female; Follow-Up Studies; Glioma - genetics; Glioma - metabolism; Glioma - mortality; Glioma - pathology; Humans; Immunoenzyme Techniques; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Male; Medicine; Medicine & Public Health; Middle Aged; Mutation - genetics; Neoplasm Grading; Neurology; Oncology; Prognosis; Proto-Oncogene Proteins c-myc - metabolism; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Survival Rate; Tissue Array Analysis; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1007/s11060-013-1221-4

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 %, χ 2 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.