Journal of Neuro-Oncology

, Volume 115, Issue 2, pp 249–259 | Cite as

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

  • Yazmin Odia
  • Brent A. Orr
  • W. Robert Bell
  • Charles G. Eberhart
  • Fausto J. Rodriguez
Clinical Study


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 %, χ2p = 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.


cMYC IDH1 IDH1 (R132H) Gliomas Glioblastoma Astrocytoma Prognosis Survival 

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Supplementary material (PPT 382 kb)


  1. 1.
    Dolecek TA, Propp JM, Stroup NE, Kruchko C (2012) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol 14:v1–v49. doi:10.1093/neuonc/nos218 PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Louis D, Ohgaki H, Wiestler O, Cavenee W, Burger P, Jouvet A, Scheithauer B, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. doi:10.1007/s00401-007-0243-4 PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre P-L, Burkhard C, Schüler D, Probst-Hensch NM, Maiorka PC, Baeza N, Pisani P, Yonekawa Y, Yasargil MG, Lütolf UM, Kleihues P (2004) Genetic pathways to glioblastoma: a population-based study. Cancer Res 64:6892–6899. doi:10.1158/0008-5472.can-04-1337 PubMedCrossRefGoogle Scholar
  4. 4.
    Capper D, Weissert S, Balss J, Habel A, Meyer J, Jäger D, Ackermann U, Tessmer C, Korshunov A, Zentgraf H, Hartmann C, Von Deimling A (2010) Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol 20:245–254. doi:10.1111/j.1750-3639.2009.00352.x PubMedCrossRefGoogle Scholar
  5. 5.
    Capper D, Zentgraf H, Balss J, Hartmann C, von Deimling A (2009) Monoclonal antibody specific for IDH-R132H mutation. Acta Neuropathol 118:599–601. doi:10.1007/s00401-009-0595-z PubMedCrossRefGoogle Scholar
  6. 6.
    Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:765–773. doi:10.1056/NEJMoa0808710 PubMedCentralPubMedCrossRefGoogle Scholar
  7. 7.
    Yang H, Ye D, Guan KL, Xiong Y (2012) IDH1 and IDH2 mutations in tumorigenesis: mechanistic insights and clinical perspectives. Clin Cancer Res 18:5562–5571. doi:10.1158/1078-0432.ccr-12-1773 PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JEC, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003. doi:10.1056/NEJMoa043331 PubMedCrossRefGoogle Scholar
  9. 9.
    Paz MF, Yaya-Tur R, Rojas-Marcos I, Reynes G, Pollan M, Aguirre-Cruz L, García-Lopez JL, Piquer J, Safont M-J, Balaña C, Sanchez-Cespedes M, García-Villanueva M, Arribas L, Esteller M (2004) CpG island hypermethylation of the DNA repair enzyme methyltransferase predicts response to temozolomide in primary gliomas. Clin Cancer Res 10:4933–4938. doi:10.1158/1078-0432.ccr-04-0392 PubMedCrossRefGoogle Scholar
  10. 10.
    Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, Silver JS, Stark PC, Macdonald DR, Ino Y, Ramsay DA, Louis DN (1998) Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 90:1473–1479. doi:10.1093/jnci/90.19.1473 PubMedCrossRefGoogle Scholar
  11. 11.
    Hartmann C, Hentschel B, Wick W, Capper D, Felsberg J, Simon M, Westphal M, Schackert G, Meyermann R, Pietsch T, Reifenberger G, Weller M, Loeffler M, von Deimling A (2010) Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas. Acta Neuropathol 120:707–718. doi:10.1007/s00401-010-0781-z PubMedCrossRefGoogle Scholar
  12. 12.
    Miller DM, Thomas SD, Islam A, Muench D, Sedoris K (2012) c-Myc and cancer metabolism. Clin Cancer Res 18:5546–5553. doi:10.1158/1078-0432.ccr-12-0977 PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Wang J, Wang H, Li Z, Wu Q, Lathia JD, McLendon RE, Hjelmeland AB, Rich JN (2008) c-Myc is required for maintenance of glioma cancer stem cells. PLoS One 3:e3769. doi:10.1371/journal.pone.0003769 PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Zheng H, Ying H, Yan H, Kimmelman AC, Hiller DJ, Chen AJ, Perry SR, Tonon G, Chu GC, Ding Z, Stommel JM, Dunn KL, Wiedemeyer R, You MJ, Brennan C, Wang YA, Ligon KL, Wong WH, Chin L, dePinho RA (2008) Pten and p53 converge on c-Myc to control differentiation, self-renewal, and transformation of normal and neoplastic stem cells in glioblastoma. Cold Spring Harb Symp Quant Biol 73:427–437. doi:10.1101/sqb.2008.73.047 PubMedCrossRefGoogle Scholar
  15. 15.
    Dang CV, Le A, Gao P (2009) MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clin Cancer Res 15:6479–6483. doi:10.1158/1078-0432.CCR-09-0889 PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Filipp F, Scott D, Ronai ZA, Osterman A, Smith J (2012) Reverse TCA cycle flux through isocitrate dehydrogenases 1 and 2 is required for lipogenesis in hypoxic melanoma cells. Pigment Cell Melanoma Res 25:375–383PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Metallo C, Gameiro P, Bell E, Mattaini K, Yang J, Hiller K, Jewell C, Johnson Z, Irvine D, Guarente L, Kelleher J, Vander Heiden M, Iliopoulos O, Stephanopoulos G (2012) Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:380–384Google Scholar
  18. 18.
    Wise D, Ward P, Shay JES, Cross J, Gruber J, Sachdeva U, Platt J, DeMatteo R, Simon MC, Thompson C (2011) Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of α-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci USA 108:19611–19616PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Yang C, Sudderth J, Dang T, Bachoo RG, McDonald JG, DeBerardinis RJ (2009) Glioblastoma cells require glutamate dehydrogenase to survive impairments of glucose metabolism or Akt signaling. Cancer Res 69:7986–7993. doi:10.1158/0008-5472.can-09-2266 PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Jenkins RB, Xiao Y, Sicotte H, Decker PA, Kollmeyer TM, Hansen HM, Kosel ML, Zheng S, Walsh KM, Rice T, Bracci P, McCoy LS, Smirnov I, Patoka JS, Hsuang G, Wiemels JL, Tihan T, Pico AR, Prados MD, Chang SM, Berger MS, Caron AA, Fink SR, Halder C, Rynearson AL, Fridley BL, Buckner JC, O’Neill BP, Giannini C, Lachance DH, Wiencke JK, Eckel-Passow JE, Wrensch MR (2012) A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation. Nat Genet 44:1122–1125. doi:10.1038/ng.2388 PubMedCentralPubMedCrossRefGoogle Scholar
  21. 21.
    Kononen J, Bubendorf L, Kallionimeni A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallionimeni O-P (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847PubMedCrossRefGoogle Scholar
  22. 22.
    Gurel B, Iwata T, Koh CM, Jenkins RB, Lan F, Van Dang C, Hicks JL, Morgan J, Cornish TC, Sutcliffe S, Isaacs WB, Luo J, De Marzo AM (2008) Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol 21:1156–1167PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Stearns D, Chaudhry A, Abel TW, Burger PC, Dang CV, Eberhart CG (2006) c-Myc overexpression causes anaplasia in medulloblastoma. Cancer Res 66:673–681. doi:10.1158/0008-5472.can-05-1580 PubMedCrossRefGoogle Scholar
  24. 24.
    Nguyen DN, Heaphy CM, de Wilde RF, Orr BA, Odia Y, Eberhart CG, Meeker AK, Rodriguez FJ (2013) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol 23:237–243. doi:10.1111/j.1750-3639.2012.00630.x PubMedCrossRefGoogle Scholar
  25. 25.
    Rodriguez F, Scheithauer B, Giannini C, Bryant S, Jenkins R (2008) Epithelial and pseudoepithelial differentiation in glioblastoma and gliosarcoma: a comparative morphologic and molecular genetic study. Cancer 113:2779–2789PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Bethel C, Faith D, Li X, Guan B, Hicks J, Lan F, Jenkins R, Bieberich C, De Marzo A (2006) Decreased NKX3.1 protein expression in focal prostatic atrophy, prostatic intraepithelial neoplasia, and adenocarcinoma: association with gleason score and chromosome 8p deletion. Cancer Res 66:10683–10690PubMedCrossRefGoogle Scholar
  27. 27.
    Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Gabrielson E, Netto GJ, Epstein JI, Lotan TL, Westra WH, Shih Ie M, Iacobuzio-Donahue CA, Maitra A, Li QK, Eberhart CG, Taube JM, Rakheja D, Kurman RJ, Wu TC, Roden RB, Argani P, De Marzo AM, Terracciano L, Torbenson M, Meeker AK (2011) Prevalence of the alternative lengthening of telomeres telomere maintenance mechanism in human cancer subtypes. Am J Pathol 179:1608–1615. doi:10.1016/j.ajpath.2011.06.018 PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Chin L, Meyerson M (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061–1068 Google Scholar
  29. 29.
    Heaphy CM, de Wilde RF, Jiao Y, Klein AP, Edil BH, Shi C, Bettegowda C, Rodriguez FJ, Eberhart CG, Hebbar S, Offerhaus GJ, McLendon R, Rasheed BA, He Y, Yan H, Bigner DD, Oba-Shinjo SM, Marie SK, Riggins GJ, Kinzler KW, Vogelstein B, Hruban RH, Maitra A, Papadopoulos N, Meeker AK (2011) Altered telomeres in tumors with ATRX and DAXX mutations. Science 333:425. doi:10.1126/science.1207313 PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Jiao Y, Killela PJ, Reitman ZJ, Rasheed AB, Heaphy CM, de Wilde RF, Rodriguez FJ, Rosemberg S, Oba-Shinjo SM, Nagahashi Marie SK, Bettegowda C, Agrawal N, Lipp E, Pirozzi C, Lopez G, He Y, Friedman H, Friedman AH, Riggins GJ, Holdhoff M, Burger P, McLendon R, Bigner DD, Vogelstein B, Meeker AK, Kinzler KW, Papadopoulos N, Diaz LA, Yan H (2012) Frequent ATRX, CIC, and FUBP1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722PubMedCentralPubMedGoogle Scholar
  31. 31.
    Nguyen DN, Heaphy CM, de Wilde RF, Orr BA, Odia Y, Eberhart CG, Meeker AK, Rodriguez FJ (2012) Molecular and morphologic correlates of the alternative lengthening of telomeres phenotype in high-grade astrocytomas. Brain Pathol. doi:10.1111/j.1750-3639.2012.00630.x PubMedCentralPubMedGoogle Scholar
  32. 32.
    Gorovets D, Kannan K, Shen R, Kastenhuber ER, Islamdoust N, Campos C, Pentsova E, Heguy A, Jhanwar SC, Mellinghoff IK, Chan TA, Huse JT (2012) IDH mutation and neuroglial developmental features define clinically distinct subclasses of lower grade diffuse astrocytic glioma. Clin Cancer Res 18:2490–2501. doi:10.1158/1078-0432.ccr-11-2977 PubMedCrossRefGoogle Scholar
  33. 33.
    Faria M, Khayat A, Burbano R, Rabenhorst S (2008) c-MYC amplification and expression in astrocytic tumors. Acta Neuropathol 116:87–95PubMedCrossRefGoogle Scholar
  34. 34.
    Faria MH, Gonçalves BP, do Patrocínio RM, de Moraes-Filho MO, Rabenhorst SH (2006) Expression of Ki-67, topoisomerase IIalpha; and c-MYC in astrocytic tumors: correlation with the histopathological grade and proliferative status. Neuropathology 26:519–527PubMedCrossRefGoogle Scholar
  35. 35.
    Frenel J, Leux C, Loussouarn D, Le Loupp A, Leclair F, Von Deimling A, Aumont M, Martin S, Denis MG, Campone M (2012) Predictive value of IDH1 mutation assessed by immunohistochemistry and DNA sequencing in WHO grade 3 oligodendrogliomas. ASCO Annual Meeting: Abstract #2002Google Scholar
  36. 36.
    Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annu Rev Pathol 3:341–365. doi:10.1146/annurev.pathmechdis.3.121806.151518 PubMedCrossRefGoogle Scholar
  37. 37.
    Turcan S, Rohle D, Goenka A, Walsh LA, Fang F, Yilmaz E, Campos C, Fabius AW, Lu C, Ward PS, Thompson CB, Kaufman A, Guryanova O, Levine R, Heguy A, Viale A, Morris LG, Huse JT, Mellinghoff IK, Chan TA (2012) IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:479–483. doi:10.1038/nature10866 PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Seltzer MJ, Bennett BD, Joshi AD, Gao P, Thomas AG, Ferraris DV, Tsukamoto T, Rojas CJ, Slusher BS, Rabinowitz JD, Dang CV, Riggins GJ (2010) Inhibition of glutaminase preferentially slows growth of glioma cells with mutant IDH1. Cancer Res 70:8981–8987. doi:10.1158/0008-5472.CAN-10-1666 PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Raabe EH, Eberhart CG (2010) High-risk medulloblastoma: does c-myc amplification overrule histopathology? Pediatr Blood Cancer 54:344–345PubMedCrossRefGoogle Scholar
  40. 40.
    Kitange G, Misra A, Law M, Passe S, Kollmeyer TM, Maurer M, Ballman K, Feuerstein BG, Jenkins RB (2005) Chromosomal imbalances detected by array comparative genomic hybridization in human oligodendrogliomas and mixed oligoastrocytomas. Genes Chromosomes Cancer 42:68–77. doi:10.1002/gcc.20108 PubMedCrossRefGoogle Scholar
  41. 41.
    Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SKN, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW (2011) Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333:1453–1455. doi:10.1126/science.1210557 PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Hsiao HH, Nath A, Lin CY, Folta Stogniew E, Rhoades E, Braddock D (2010) Quantitative characterization of the interactions among c-myc transcriptional regulators FUSE, FBP, and FIR. Biochemistry 49:4620–4634PubMedCrossRefGoogle Scholar
  43. 43.
    Takwi AA, Li Y, Becker Buscaglia LE, Zhang J, Choudhury S, Park AK, Liu M, Young KH, Park WY, Martin RC (2012) A statin-regulated microRNA represses human c-Myc expression and function. EMBO Mol Med 4:896–909. doi:10.1002/emmm.201101045 PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, Petrelli NJ, Dunn SP, Krueger LJ (2007) MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res 67:9762–9770. doi:10.1158/0008-5472.CAN-07-2462 PubMedCrossRefGoogle Scholar
  45. 45.
    Lujambio A, Calin GA, Villanueva A, Ropero S, Sanchez-Cespedes M, Blanco D, Montuenga LM, Rossi S, Nicoloso MS, Faller WJ, Gallagher WM, Eccles SA, Croce CM, Esteller M (2008) A microRNA DNA methylation signature for human cancer metastasis. Proc Natl Acad Sci USA 105:13556–13561. doi:10.1073/pnas.0803055105 PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Yazmin Odia
    • 1
    • 4
  • Brent A. Orr
    • 2
    • 5
  • W. Robert Bell
    • 2
  • Charles G. Eberhart
    • 2
    • 3
  • Fausto J. Rodriguez
    • 2
    • 3
  1. 1.Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Division of Neuropathology, Department of PathologyJohns Hopkins Hospital, The Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Neuro-Oncology BranchNational Cancer InstituteBethesdaUSA
  5. 5.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA

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