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Journal of Neuro-Oncology

, Volume 127, Issue 2, pp 363–372 | Cite as

IDH mutation is associated with higher risk of malignant transformation in low-grade glioma

  • Severina Leu
  • Stefanie von Felten
  • Stephan Frank
  • Jean-Louis Boulay
  • Luigi Mariani
Clinical Study

Abstract

Acquisition of IDH1 or IDH2 mutation (IDHmut) is among the earliest genetic events that take place in the development of most low-grade glioma (LGG). IDHmut has been associated with longer overall patient survival. However, its impact on malignant transformation (MT) remains to be defined. A collection of 210 archived adult LGG previously stratified by IDHmut, MGMT methylation (MGMTmet), 1p/19q combined loss of heterozygosity (1p19qloh) and TP53 immunopositivity (TP53pos) status was analyzed. We used multistate models to assess MT-free survival, considering one initial, one transient (MT), and one absorbing state (death). Missing explanatory variables were multiply imputed. Overall, although associated with a lower risk of death (HRDEATH = 0.35, P = 0.0023), IDHmut had a non-significantly higher risk of MT (HRMT = 1.84; P = 0.1683) compared to IDH wild type (IDHwt). The double combination of IDHmut and MGMTmet and the triple combination of IDHmut, MGMTmet and 1p/19qloh, despite significantly lower hazards for death (HRDEATH versus IDHwt: 0.35, P = 0.0194 and 0.15, P = 0.0008, respectively), had non-significantly different hazards for MT. Conversely, the triple combination of IDHmut/MGMTmet/TP53pos, with a non-significantly different hazard for death, had a significantly higher hazard for MT than IDHwt (HRMT versus IDHwt: 2.83; P = 0.0452). Although IDHmut status is associated with longer overall patient survival, all IDHmut/MGMTmet subsets consistently showed higher risks of MT than of death, compared to IDHwt LGG. This supports the findings that molecular events relevant to IDH mutations impact early glioma development prior to malignant transformation.

Keywords

Brain tumor Survival Biomarker MGMT Gliomagenesis 

Notes

Acknowledgments

This work was supported by The Swiss Cancer League (Grant KLS 2765-02-2011 to JLB, LM, and SF).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Supplementary material

11060_2015_2048_MOESM1_ESM.docx (22 kb)
Supplementary material 1 (DOCX 21 kb)
11060_2015_2048_MOESM2_ESM.pdf (40 kb)
Supplementary material 2 (PDF 39 kb)
11060_2015_2048_MOESM3_ESM.docx (28 kb)
Supplementary material 3 (DOCX 28 kb)

References

  1. 1.
    Kleihues P, Burger PC, Scheithauer BW (1993) The new WHO classification of brain tumours. Brain Pathol 3:255–268CrossRefPubMedGoogle Scholar
  2. 2.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, 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 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M, Schüler D, Probst-Hensch NM, Yasargil MG, Yonekawa Y, Lütolf UM, Kleihues P, Ohgaki H (2004) Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol 108:49–56. doi: 10.1007/s00401-004-0861-z CrossRefPubMedGoogle Scholar
  4. 4.
    Ohgaki H, Kleihues P (2005) Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. J Neuropathol Exp Neurol 64:479–489CrossRefPubMedGoogle Scholar
  5. 5.
    Leighton C, Fisher B, Bauman G, Depiero S, Stitt L, MacDonald D, Cairncross G (1997) Supratentorial low-grade glioma in adults: an analysis of prognostic factors and timing of radiation. J Clin Oncol 15:1294–1301PubMedGoogle Scholar
  6. 6.
    Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, Afra D, Cornu P, Bolla M, Vecht C, Karim AB, Group EOfRaToCBTC, Group EOfRaToCRC (2002) Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084CrossRefPubMedGoogle Scholar
  7. 7.
    Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812. doi: 10.1126/science.1164382 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Noushmehr H, Weisenberger DJ, Diefes K, Phillips HS, Pujara K, Berman BP, Pan F, Pelloski CE, Sulman EP, Bhat KP, Verhaak RG, Hoadley KA, Hayes DN, Perou CM, Schmidt HK, Ding L, Wilson RK, Van Den Berg D, Shen H, Bengtsson H, Neuvial P, Cope LM, Buckley J, Herman JG, Baylin SB, Laird PW, Aldape K, Network CGAR (2010) Identification of a CpG island methylator phenotype that defines a distinct subgroup of glioma. Cancer Cell 17:510–522. doi: 10.1016/j.ccr.2010.03.017 CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Sanson M, Marie Y, Paris S, Idbaih A, Laffaire J, Ducray F, El Hallani S, Boisselier B, Mokhtari K, Hoang-Xuan K, Delattre JY (2009) Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol 27:4150–4154. doi: 10.1200/JCO.2009.21.9832 CrossRefPubMedGoogle Scholar
  11. 11.
    Houillier C, Wang X, Kaloshi G, Mokhtari K, Guillevin R, Laffaire J, Paris S, Boisselier B, Idbaih A, Laigle-Donadey F, Hoang-Xuan K, Sanson M, Delattre JY (2010) IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas. Neurology 75:1560–1566. doi: 10.1212/WNL.0b013e3181f96282 CrossRefPubMedGoogle Scholar
  12. 12.
    Dubbink HJ, Taal W, van Marion R, Kros JM, van Heuvel I, Bromberg JE, Zonnenberg BA, Zonnenberg CB, Postma TJ, Gijtenbeek JM, Boogerd W, Groenendijk FH, Smitt PA, Dinjens WN, van den Bent MJ (2009) IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide. Neurology 73:1792–1795. doi: 10.1212/WNL.0b013e3181c34ace CrossRefPubMedGoogle Scholar
  13. 13.
    Mellai M, Piazzi A, Caldera V, Monzeglio O, Cassoni P, Valente G, Schiffer D (2011) IDH1 and IDH2 mutations, immunohistochemistry and associations in a series of brain tumors. J Neurooncol 105:345–357. doi: 10.1007/s11060-011-0596-3 CrossRefPubMedGoogle Scholar
  14. 14.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, 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 CrossRefPubMedGoogle Scholar
  15. 15.
    Nobusawa S, Watanabe T, Kleihues P, Ohgaki H (2009) IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 15:6002–6007. doi: 10.1158/1078-0432.CCR-09-0715 CrossRefPubMedGoogle Scholar
  16. 16.
    Zou P, Xu H, Chen P, Yan Q, Zhao L, Zhao P, Gu A (2013) IDH1/IDH2 mutations define the prognosis and molecular profiles of patients with gliomas: a meta-analysis. PLoS ONE 8:e68782. doi: 10.1371/journal.pone.0068782 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Watanabe T, Nobusawa S, Kleihues P, Ohgaki H (2009) IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol 174:1149–1153. doi: 10.2353/ajpath.2009.080958 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Kim YH, Nobusawa S, Mittelbronn M, Paulus W, Brokinkel B, Keyvani K, Sure U, Wrede K, Nakazato Y, Tanaka Y, Vital A, Mariani L, Stawski R, Watanabe T, De Girolami U, Kleihues P, Ohgaki H (2010) Molecular classification of low-grade diffuse gliomas. Am J Pathol 177:2708–2714. doi: 10.2353/ajpath.2010.100680 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Mariani L, Deiana G, Vassella E, Fathi AR, Murtin C, Arnold M, Vajtai I, Weis J, Siegenthaler P, Schobesberger M, Reinert MM (2006) Loss of heterozygosity 1p36 and 19q13 is a prognostic factor for overall survival in patients with diffuse WHO grade 2 gliomas treated without chemotherapy. J Clin Oncol 24:4758–4763. doi: 10.1200/JCO.2006.05.9238 CrossRefPubMedGoogle Scholar
  20. 20.
    Leu S, von Felten S, Frank S, Vassella E, Vajtai I, Taylor E, Schulz M, Hutter G, Hench J, Schucht P, Boulay JL, Mariani L (2013) IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival. Neuro Oncol 15:469–479. doi: 10.1093/neuonc/nos317 CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, Su SM (2009) Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature 462:739–744. doi: 10.1038/nature08617 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, Edwards CR, Khanin R, Figueroa ME, Melnick A, Wellen KE, O’Rourke DM, Berger SL, Chan TA, Levine RL, Mellinghoff IK, Thompson CB (2012) IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature 483:474–478. doi: 10.1038/nature10860 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    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 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Costello JF, Futscher BW, Tano K, Graunke DM, Pieper RO (1994) Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. J Biol Chem 269:17228–17237PubMedGoogle Scholar
  25. 25.
    Ohgaki H, Dessen P, Jourde B, Horstmann S, Nishikawa T, Di Patre PL, 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 CrossRefPubMedGoogle Scholar
  26. 26.
    Odia Y, Orr BA, Bell WR, Eberhart CG, Rodriguez FJ (2013) cMYC expression in infiltrating gliomas: associations with IDH1 mutations, clinicopathologic features and outcome. J Neurooncol 115:249–259. doi: 10.1007/s11060-013-1221-4 CrossRefPubMedGoogle Scholar
  27. 27.
    Wakimoto H, Tanaka S, Curry WT, Loebel F, Zhao D, Tateishi K, Chen J, Klofas LK, Lelic N, Kim JC, Dias-Santagata D, Ellisen LW, Borger DR, Fendt SM, Vander Heiden MG, Batchelor TT, Iafrate AJ, Cahill DP, Chi AS (2014) Targetable signaling pathway mutations are associated with malignant phenotype in IDH-mutant gliomas. Clin Cancer Res 20:2898–2909. doi: 10.1158/1078-0432.CCR-13-3052 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    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 SK, 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 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, Cooper LA, Rheinbay E, Miller CR, Vitucci M, Morozova O, Robertson AG, Noushmehr H, Laird PW, Cherniack AD, Akbani R, Huse JT, Ciriello G, Poisson LM, Barnholtz-Sloan JS, Berger MS, Brennan C, Colen RR, Colman H, Flanders AE, Giannini C, Grifford M, Iavarone A, Jain R, Joseph I, Kim J, Kasaian K, Mikkelsen T, Murray BA, O’Neill BP, Pachter L, Parsons DW, Sougnez C, Sulman EP, Vandenberg SR, Van Meir EG, von Deimling A, Zhang H, Crain D, Lau K, Mallery D, Morris S, Paulauskis J, Penny R, Shelton T, Sherman M, Yena P, Black A, Bowen J, Dicostanzo K, Gastier-Foster J, Leraas KM, Lichtenberg TM, Pierson CR, Ramirez NC, Taylor C, Weaver S, Wise L, Zmuda E, Davidsen T, Demchok JA, Eley G, Ferguson ML, Hutter CM, Mills Shaw KR, Ozenberger BA, Sheth M, Sofia HJ, Tarnuzzer R, Wang Z, Yang L, Zenklusen JC, Ayala B, Baboud J, Chudamani S, Jensen MA, Liu J, Pihl T, Raman R, Wan Y, Wu Y, Ally A, Auman JT, Balasundaram M, Balu S, Baylin SB, Beroukhim R, Bootwalla MS, Bowlby R, Bristow CA, Brooks D, Butterfield Y, Carlsen R, Carter S, Chin L, Chu A, Chuah E, Cibulskis K, Clarke A, Coetzee SG, Dhalla N, Fennell T, Fisher S, Gabriel S, Getz G, Gibbs R, Guin R, Hadjipanayis A, Hayes DN, Hinoue T, Hoadley K, Holt RA, Hoyle AP, Jefferys SR, Jones S, Jones CD, Kucherlapati R, Lai PH, Lander E, Lee S, Lichtenstein L, Ma Y, Maglinte DT, Mahadeshwar HS, Marra MA, Mayo M, Meng S, Meyerson ML, Mieczkowski PA, Moore RA, Mose LE, Mungall AJ, Pantazi A, Parfenov M, Park PJ, Parker JS, Perou CM, Protopopov A, Ren X, Roach J, Sabedot TS, Schein J, Schumacher SE, Seidman JG, Seth S, Shen H, Simons JV, Sipahimalani P, Soloway MG, Song X, Sun H, Tabak B, Tam A, Tan D, Tang J, Thiessen N, Triche T, Van Den Berg DJ, Veluvolu U, Waring S, Weisenberger DJ, Wilkerson MD, Wong T, Wu J, Xi L, Xu AW, Zack TI, Zhang J, Aksoy BA, Arachchi H, Benz C, Bernard B, Carlin D, Cho J, DiCara D, Frazer S, Fuller GN, Gao J, Gehlenborg N, Haussler D, Heiman DI, Iype L, Jacobsen A, Ju Z, Katzman S, Kim H, Knijnenburg T, Kreisberg RB, Lawrence MS, Lee W, Leinonen K, Lin P, Ling S, Liu W, Liu Y, Lu Y, Mills G, Ng S, Noble MS, Paull E, Rao A, Reynolds S, Saksena G, Sanborn Z, Sander C, Schultz N, Senbabaoglu Y, Shen R, Shmulevich I, Sinha R, Stuart J, Sumer SO, Sun Y, Tasman N, Taylor BS, Voet D, Weinhold N, Weinstein JN, Yang D, Yoshihara K, Zheng S, Zhang W, Zou L, Abel T, Sadeghi S, Cohen ML, Eschbacher J, Hattab EM, Raghunathan A, Schniederjan MJ, Aziz D, Barnett G, Barrett W, Bigner DD, Boice L, Brewer C, Calatozzolo C, Campos B, Carlotti CG, Chan TA, Cuppini L, Curley E, Cuzzubbo S, Devine K, DiMeco F, Duell R, Elder JB, Fehrenbach A, Finocchiaro G, Friedman W, Fulop J, Gardner J, Hermes B, Herold-Mende C, Jungk C, Kendler A, Lehman NL, Lipp E, Liu O, Mandt R, McGraw M, Mclendon R, McPherson C, Neder L, Nguyen P, Noss A, Nunziata R, Ostrom QT, Palmer C, Perin A, Pollo B, Potapov A, Potapova O, Rathmell WK, Rotin D, Scarpace L, Schilero C, Senecal K, Shimmel K, Shurkhay V, Sifri S, Singh R, Sloan AE, Smolenski K, Staugaitis SM, Steele R, Thorne L, Tirapelli DP, Unterberg A, Vallurupalli M, Wang Y, Warnick R, Williams F, Wolinsky Y, Bell S, Rosenberg M, Stewart C, Huang F, Grimsby JL, Radenbaugh AJ, Network CGAR (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498. doi: 10.1056/NEJMoa1402121 CrossRefPubMedGoogle Scholar
  30. 30.
    Eckel-Passow JE, Lachance DH, Molinaro AM, Walsh KM, Decker PA, Sicotte H, Pekmezci M, Rice T, Kosel ML, Smirnov IV, Sarkar G, Caron AA, Kollmeyer TM, Praska CE, Chada AR, Halder C, Hansen HM, McCoy LS, Bracci PM, Marshall R, Zheng S, Reis GF, Pico AR, O’Neill BP, Buckner JC, Giannini C, Huse JT, Perry A, Tihan T, Berger MS, Chang SM, Prados MD, Wiemels J, Wiencke JK, Wrensch MR, Jenkins RB (2015) Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499–2508. doi: 10.1056/NEJMoa1407279 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    van Buuren S, Groothuis-Oudshoorn K, (2011) MICE: multivariate imputation by chained equations in R. Journal of statistical software, pp 1–67Google Scholar
  32. 32.
    Core Team R (2012) R: a language and environment for statistical computing. R Foundation for Statistical Computing, ViennaGoogle Scholar
  33. 33.
    Rubin D (1987) Multiple imputation for nonresponse in surveys. John Willey and Sons, New YorkCrossRefGoogle Scholar
  34. 34.
    Putter H, Fiocco M, Geskus RB (2007) Tutorial in biostatistics: competing risks and multi-state models. Stat Med 26:2389–2430. doi: 10.1002/sim.2712 CrossRefPubMedGoogle Scholar
  35. 35.
    Persson I, Khamis H (2005) Bias of the Cox model hazard ratio. J Mod Appl Stat Method 4:90–99Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Severina Leu
    • 2
  • Stefanie von Felten
    • 3
  • Stephan Frank
    • 4
  • Jean-Louis Boulay
    • 1
  • Luigi Mariani
    • 1
    • 2
  1. 1.Laboratory of Brain Tumor Biology, Department of BiomedicineUniversity Hospital BaselBaselSwitzerland
  2. 2.Neurosurgery ClinicUniversity Hospital BaselBaselSwitzerland
  3. 3.Clinical Trial UnitUniversity Hospital BaselBaselSwitzerland
  4. 4.Division of Neuropathology, Institute of PathologyUniversity Hospital BaselBaselSwitzerland

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