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Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors

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Abstract

Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP− tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP−), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP− subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP−) prognosis. Furthermore, transcriptomic analyses revealed CIMP-specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs.

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References

  1. Alonso ME, Bello MJ, Gonzalez-Gomez P, Arjona D, Lomas J, de Campos JM, Isla A, Sarasa JL, Rey JA (2003) Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. Cancer Genet Cytogenet 144:134–142

    Article  PubMed  CAS  Google Scholar 

  2. Bady P, Sciuscio D, Diserens AC, Bloch J, van den Bent MJ, Marosi C, Dietrich PY, Weller M, Mariani L, Heppner FL, Mcdonald DR, Lacombe D, Stupp R, Delorenzi M, Hegi ME (2012) MGMT methylation analysis of glioblastoma on the infinium methylation beadchip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status. Acta Neuropathol 124:547–560

    Article  PubMed  CAS  Google Scholar 

  3. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A (2008) Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol 116:597–602

    Article  PubMed  CAS  Google Scholar 

  4. Bello MJ, Leone PE, Vaquero J, de Campos JM, Kusak ME, Sarasa JL, Pestaña A, Rey JA (1995) Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors. Int J Cancer 64:207–210

    Article  PubMed  CAS  Google Scholar 

  5. 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

    Article  PubMed  CAS  Google Scholar 

  6. Blesa D, Mollejo M, Ruano Y, de Lope AR, Fiaño C, Ribalta T, García JF, Campos-Martín Y, Hernández-Moneo JL, Cigudosa JC, Meléndez B (2009) Novel genomic alterations and mechanisms associated with tumor progression in oligodendroglioma and mixed oligoastrocytoma. J Neuropathol Exp Neurol 68:274–285

    Article  PubMed  CAS  Google Scholar 

  7. Brellier F, Ruggiero S, Zwolanek D, Martina E, Hess D, Brown-Luedi M, Hartmann U, Koch M, Merlo A, Lino M, Chiquet-Ehrismann R (2011) SMOC1 is a tenascin-C interacting protein over-expressed in brain tumors. Matrix Biol 30:225–233

    Article  PubMed  CAS  Google Scholar 

  8. 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

    Article  PubMed  CAS  Google Scholar 

  9. Chou AP, Chowdhury R, Li S, Chen W, Kim AJ, Piccioni DE, Selfridge JM, Mody RR, Chang S, Lalezari S, Lin J, Sanchez DE, Wilson RW, Garrett MC, Harry B, Mottahedeh J, Nghiemphu PL, Kornblum HI, Mischel PS, Prins RM, Yong WH, Cloughesy T, Nelson SF, Liau LM, Lai A (2012) Identification of retinol binding protein 1 promoter hypermethylation in isocitrate dehydrogenase 1 and 2 mutant gliomas. J Natl Cancer Inst 104:1458–1469

    Article  PubMed  CAS  Google Scholar 

  10. Curtin K, Slattery ML, Samowitz WS (2011) CpG island methylation in colorectal cancer: past, present and future. Pathol Res Int 2011:902674

    Google Scholar 

  11. Dittmann LM, Danner A, Gronych J, Wolter M, Stühler K, Grzendowski M, Becker N, Bageritz J, Goidts V, Toedt G, Felsberg J, Sabel MC, Barbus S, Reifenberger G, Lichter P, Tews B (2012) Downregulation of PRDX1 by promoter hypermethylation is frequent in 1p/19q-deleted oligodendroglial tumours and increases radio- and chemosensitivity of Hs683 glioma cells in vitro. Oncogene 31:3409–3418

    Article  PubMed  CAS  Google Scholar 

  12. Ducray F, Marie Y, Sanson M (2009) IDH1 and IDH2 mutations in gliomas. N Engl J Med 360:2248–2249 (author reply 2249)

    Article  PubMed  CAS  Google Scholar 

  13. Duncan CG, Barwick BG, Jin G, Rago C, Kapoor-Vazirani P, Powell DR, Chi JT, Bigner DD, Vertino PM, Yan H (2012) A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation. Genome Res 22:2339–2355

    Article  PubMed  CAS  Google Scholar 

  14. Esteller M (2008) Epigenetics in cancer. N Engl J Med 358:1148–1159

    Article  PubMed  CAS  Google Scholar 

  15. French PJ, Swagemakers SM, Nagel JH, Kouwenhoven MC, Brouwer E, van der Spek P, Luider TM, Kros JM, van den Bent MJ, Sillevis Smitt PA (2005) Gene expression profiles associated with treatment response in oligodendrogliomas. Cancer Res 65:11335–11344

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. Griffin CA, Burger P, Morsberger L, Yonescu R, Swierczynski S, Weingart JD, Murphy KM (2006) Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 65:988–994

    Article  PubMed  Google Scholar 

  18. Hartmann C, Meyer J, Balss J, Capper D, Mueller W, Christians A, Felsberg J, Wolter M, Mawrin C, Wick W, Weller M, Herold-Mende C, Unterberg A, Jeuken JW, Wesseling P, Reifenberger G, von Deimling A (2009) Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 118:469–474

    Article  PubMed  Google Scholar 

  19. Hassler MR, Egger G (2012) Epigenomics of cancer—emerging new concepts. Biochimie 94:2219–2230

    Article  PubMed  CAS  Google Scholar 

  20. 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

    Article  PubMed  CAS  Google Scholar 

  21. Huang dW, Sherman BT, Lempicki RA (2009) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4:44–57

    Article  CAS  Google Scholar 

  22. Issa JP, Shen L, Toyota M (2005) CIMP, at last. Gastroenterology 129:1121–1124

    Article  PubMed  CAS  Google Scholar 

  23. Jenkins RB, Blair H, Ballman KV, Giannini C, Arusell RM, Law M, Flynn H, Passe S, Felten S, Brown PD, Shaw EG, Buckner JC (2006) A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res 66:9852–9861

    Article  PubMed  CAS  Google Scholar 

  24. 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, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 3:709–722

    PubMed  Google Scholar 

  25. Kannan K, Inagaki A, Silber J, Gorovets D, Zhang J, Kastenhuber ER, Heguy A, Petrini JH, Chan TA, Huse JT (2012) Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma. Oncotarget 3:1194–1203

    PubMed  Google Scholar 

  26. Kim W, Liau LM (2012) IDH mutations in human glioma. Neurosurg Clin N Am 23:471–480

    Article  PubMed  Google Scholar 

  27. Kraus JA, Koopmann J, Kaskel P, Maintz D, Brandner S, Schramm J, Louis DN, Wiestler OD, von Deimling A (1995) Shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and oligoastrocytoma. J Neuropathol Exp Neurol 54:91–95

    Article  PubMed  CAS  Google Scholar 

  28. Kulis M, Heath S, Bibikova M, Queirós AC, Navarro A, Clot G, Martínez-Trillos A, Castellano G, Brun-Heath I, Pinyol M, Barberán-Soler S, Papasaikas P, Jares P, Beà S, Rico D, Ecker S, Rubio M, Royo R, Ho V, Klotzle B, Hernández L, Conde L, López-Guerra M, Colomer D, Villamor N, Aymerich M, Rozman M, Bayes M, Gut M, Gelpí JL, Orozco M, Fan JB, Quesada V, Puente XS, Pisano DG, Valencia A, López-Guillermo A, Gut I, López-Otín C, Campo E, Martín-Subero JI (2012) Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat Genet 44:1236–1242

    Article  PubMed  CAS  Google Scholar 

  29. Ladi E, Nichols JT, Ge W, Miyamoto A, Yao C, Yang LT, Boulter J, Sun YE, Kintner C, Weinmaster G (2005) The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. J Cell Biol 170:983–992

    Article  PubMed  CAS  Google Scholar 

  30. Laffaire J, Everhard S, Idbaih A, Crinière E, Marie Y, de Reyniès A, Schiappa R, Mokhtari K, Hoang-Xuan K, Sanson M, Delattre JY, Thillet J, Ducray F (2011) Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. Neurol Oncol 13:84–98

    Article  CAS  Google Scholar 

  31. 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

    Article  PubMed  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. 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

    Article  PubMed  CAS  Google Scholar 

  34. Pang JC, Li KK, Lau KM, Ng YL, Wong J, Chung NY, Li HM, Chui YL, Lui VW, Chen ZP, Chan DT, Poon WS, Wang Y, Mao Y, Zhou L, Ng HK (2010) KIAA0495/PDAM is frequently downregulated in oligodendroglial tumors and its knockdown by siRNA induces cisplatin resistance in glioma cells. Brain Pathol 20:1021–1032

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. Phillips HS, Kharbanda S, Chen R, Forrest WF, Soriano RH, Wu TD, Misra A, Nigro JM, Colman H, Soroceanu L, Williams PM, Modrusan Z, Feuerstein BG, Aldape K (2006) Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9:157–173

    Article  PubMed  CAS  Google Scholar 

  37. Pérez-Magán E, Campos-Martín Y, Mur P, Fiaño C, Ribalta T, García JF, Rey JA, Rodríguez de Lope A, Mollejo M, Meléndez B (2012) Genetic alterations associated with progression and recurrence in meningiomas. J Neuropathol Exp Neurol 71:882–893

    Article  PubMed  Google Scholar 

  38. Reifenberger J, Reifenberger G, Liu L, James CD, Wechsler W, Collins VP (1994) Molecular genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am J Pathol 145:1175–1190

    PubMed  CAS  Google Scholar 

  39. Roman-Gomez J, Jimenez-Velasco A, Agirre X, Castillejo JA, Navarro G, Calasanz MJ, Garate L, San Jose-Eneriz E, Cordeu L, Prosper F, Heiniger A, Torres A (2006) CpG island methylator phenotype redefines the prognostic effect of t(12;21) in childhood acute lymphoblastic leukemia. Clin Cancer Res 12:4845–4850

    Article  PubMed  CAS  Google Scholar 

  40. Ruano Y, Ribalta T, de Lope AR, Campos-Martín Y, Fiaño C, Pérez-Magán E, Hernández-Moneo JL, Mollejo M, Meléndez B (2009) Worse outcome in primary glioblastoma multiforme with concurrent epidermal growth factor receptor and p53 alteration. Am J Clin Pathol 131:257–263

    Article  PubMed  CAS  Google Scholar 

  41. Ryan KM (2011) p53 and autophagy in cancer: guardian of the genome meets guardian of the proteome. Eur J Cancer 47:44–50

    Article  PubMed  CAS  Google Scholar 

  42. Sahm F, Koelsche C, Meyer J, Pusch S, Lindenberg K, Mueller W, Herold-Mende C, von Deimling A, Hartmann C (2012) CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol 123:853–860

    Article  PubMed  CAS  Google Scholar 

  43. Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tönjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jäger N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Frühwald MC, Roggendorf W, Kramm C, Dürken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N (2012) Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482:226–231

    Article  PubMed  CAS  Google Scholar 

  44. Smith JS, Perry A, Borell TJ, Lee HK, O’Fallon J, Hosek SM, Kimmel D, Yates A, Burger PC, Scheithauer BW, Jenkins RB (2000) Alterations of chromosome arms 1p and 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol 18:636–645

    PubMed  CAS  Google Scholar 

  45. Snuderl M, Eichler AF, Ligon KL, Vu QU, Silver M, Betensky RA, Ligon AH, Wen PY, Louis DN, Iafrate AJ (2009) Polysomy for chromosomes 1 and 19 predicts earlier recurrence in anaplastic oligodendrogliomas with concurrent 1p/19q loss. Clin Cancer Res 15:6430–6437

    Article  PubMed  CAS  Google Scholar 

  46. Sturm D, Witt H, Hovestadt V, Khuong-Quang DA, Jones DT, Konermann C, Pfaff E, Tönjes M, Sill M, Bender S, Kool M, Zapatka M, Becker N, Zucknick M, Hielscher T, Liu XY, Fontebasso AM, Ryzhova M, Albrecht S, Jacob K, Wolter M, Ebinger M, Schuhmann MU, van Meter T, Frühwald MC, Hauch H, Pekrun A, Radlwimmer B, Niehues T, von Komorowski G, Dürken M, Kulozik AE, Madden J, Donson A, Foreman NK, Drissi R, Fouladi M, Scheurlen W, von Deimling A, Monoranu C, Roggendorf W, Herold-Mende C, Unterberg A, Kramm CM, Felsberg J, Hartmann C, Wiestler B, Wick W, Milde T, Witt O, Lindroth AM, Schwartzentruber J, Faury D, Fleming A, Zakrzewska M, Liberski PP, Zakrzewski K, Hauser P, Garami M, Klekner A, Bognar L, Morrissy S, Cavalli F, Taylor MD, van Sluis P, Koster J, Versteeg R, Volckmann R, Mikkelsen T, Aldape K, Reifenberger G, Collins VP, Majewski J, Korshunov A, Lichter P, Plass C, Jabado N, Pfister SM (2012) Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22:425–437

    Article  PubMed  CAS  Google Scholar 

  47. Teodoridis JM, Hardie C, Brown R (2008) CpG island methylator phenotype (CIMP) in cancer: causes and implications. Cancer Lett 268:177–186

    Article  PubMed  CAS  Google Scholar 

  48. 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

    Article  PubMed  CAS  Google Scholar 

  49. van den Bent MJ, Gravendeel LA, Gorlia T, Kros JM, Lapre L, Wesseling P, Teepen JL, Idbaih A, Sanson M, Smitt PA, French PJ (2011) A hypermethylated phenotype is a better predictor of survival than MGMT methylation in anaplastic oligodendroglial brain tumors: a report from EORTC study 26951. Clin Cancer Res 17:7148–7155

    Article  PubMed  Google Scholar 

  50. Vaquerizas JM, Dopazo J, Díaz-Uriarte R (2004) DNMAD: web-based diagnosis and normalization for microarray data. Bioinformatics 20:3656–3658

    Article  PubMed  CAS  Google Scholar 

  51. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP, Alexe G, Lawrence M, O’Kelly M, Tamayo P, Weir BA, Gabriel S, Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN, Network CGAR (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

    Article  PubMed  CAS  Google Scholar 

  52. von Deimling A, Korshunov A, Hartmann C (2011) The next generation of glioma biomarkers: MGMT methylation, BRAF fusions and IDH1 mutations. Brain Pathol 21:74–87

    Article  Google Scholar 

  53. Ward PS, Patel J, Wise DR, Abdel-Wahab O, Bennett BD, Coller HA, Cross JR, Fantin VR, Hedvat CV, Perl AE, Rabinowitz JD, Carroll M, Su SM, Sharp KA, Levine RL, Thompson CB (2010) The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17:225–234

    Article  PubMed  CAS  Google Scholar 

  54. Weller M, Berger H, Hartmann C, Schramm J, Westphal M, Simon M, Goldbrunner R, Krex D, Steinbach JP, Ostertag CB, Loeffler M, Pietsch T, von Deimling A, Network GG (2007) Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin Cancer Res 13:6933–6937

    Article  PubMed  CAS  Google Scholar 

  55. Wiens AL, Cheng L, Bertsch EC, Johnson KA, Zhang S, Hattab EM (2012) Polysomy of chromosomes 1 and/or 19 is common and associated with less favorable clinical outcome in oligodendrogliomas: fluorescent in situ hybridization analysis of 84 consecutive cases. J Neuropathol Exp Neurol 71:618–624

    Article  PubMed  CAS  Google Scholar 

  56. Wu G, Broniscer A, McEachron TA, Lu C, Paugh BS, Becksfort J, Qu C, Ding L, Huether R, Parker M, Zhang J, Gajjar A, Dyer MA, Mullighan CG, Gilbertson RJ, Mardis ER, Wilson RK, Downing JR, Ellison DW, Baker SJ, Project SJCsRHWUPCG (2012) Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44:251–253

    Article  PubMed  CAS  Google Scholar 

  57. Wu X, Rauch TA, Zhong X, Bennett WP, Latif F, Krex D, Pfeifer GP (2010) CpG island hypermethylation in human astrocytomas. Cancer Res 70:2718–2727

    Article  PubMed  CAS  Google Scholar 

  58. 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

    Article  PubMed  CAS  Google Scholar 

  59. Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, Birol I, Chesnelong C, Chiu R, Chuah E, Corbett R, Docking R, Firme M, Hirst M, Jackman S, Karsan A, Li H, Louis DN, Maslova A, Moore R, Moradian A, Mungall KL, Perizzolo M, Qian J, Roldan G, Smith EE, Tamura-Wells J, Thiessen N, Varhol R, Weiss S, Wu W, Young S, Zhao Y, Mungall AJ, Jones SJ, Morin GB, Chan JA, Cairncross JG, Marra MA (2012) Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol 226:7–16

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We acknowledge the Spanish Tumour Bank Network of the Centro Nacional de Investigaciones Oncológicas (Madrid, Spain) and the Tumor Bank of the Hospital Virgen de la Salud (BioB-HVS, Toledo, Spain) for providing tumor samples. This work was supported by grants PI10/01974 and PI10/01972 from the Fondo de Investigaciones Sanitarias of the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, co-funded by the Fondo Europeo de Desarrollo Regional (FEDER 2007-2013); and a Castilla-La Mancha Regional grant, Ayudas a la Investigación en Biomedicina y Ciencias de la Salud (PI-2010/45).

Conflict of interest

The authors have no conflict of interest to declare.

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Authors and Affiliations

  1. Molecular Pathology Research Unit, Department of Pathology, Virgen de la Salud Hospital, Avda. Barber 30, 45004, Toledo, Spain

    Pilar Mur, Manuela Mollejo & Bárbara Meléndez

  2. Department of Pathology, Virgen de la Salud Hospital, Avda Barber 30, 45004, Toledo, Spain

    Manuela Mollejo

  3. Department of Pathology (Neuropathology), 12 de Octubre University Hospital, Avda de Córdoba s/n, 28041, Madrid, Spain

    Yolanda Ruano & Aurelio Hernández-Laín

  4. Department of Neurosurgery, Puerta del Hierro Hospital, C/Manuel de Falla no 1, Majadahonda, 28222, Madrid, Spain

    Ángel Rodríguez de Lope

  5. Department of Pathology, University Hospital Complex of Vigo (C.H.U.V.I.), Rúa Pizarro, 22, 36204, Vigo, Spain

    Concepción Fiaño

  6. Department of Pathology, MD Anderson International, C/Arturo Soria 270, 28033, Madrid, Spain

    Juan Fernando García

  7. Brain Tumor Biology Unit, University of Navarra School of Sciences, C/Irunlarrea 1, 31008, Pamplona, Spain

    Javier S. Castresana

  8. IdiPaz Research Unit, La Paz University Hospital, Po de la Castellana, 261, 28046, Madrid, Spain

    Juan A. Rey

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  1. Pilar Mur
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401_2013_1130_MOESM1_ESM.xls

Supplementary Table S1 Clinical and molecular characteristics of 55 patients with oligodendroglial tumors. Supplementary Table S2 The most differentially methylated genes between the CD-CIMP+ and CIMP+ groups within islands and shores of promoter regions. Supplementary Table S3 Differentially expressed genes between IDH-mutated and wild-type tumors (q < 0.05) Supplementary Table S4 Differentially expressed genes between 1p/19q-deleted and 1p/19q-intact tumors (q < 0.05). Supplementary Table S5 139 differentially expressed genes between the three CIMP groups showing gene expression levels (q < 0.08) (XLS 1017 kb)

401_2013_1130_MOESM2_ESM.ppt

Supplementary Fig. S1 a Unsupervised hierarchical clustering based on the 2,816 CpGs that varied most among the samples of tumors (variance = 0.7; 63 % of the variation) showing two groups of tumors with different methylation profiles (G-CIMP), which are strongly associated with IDH mutational status. b Graphical representation of selected genes associated with the IDH-mutated hypermethylator phenotype showing Avg. β methylation levels for each CpG (indicated by circles inside of the lines). The transcriptional start site is indicated by a black arrow, and areas shaded in gray represent the regions of greatest methylation differences. Methylated gene promoters (KIAA0495, RBP1, PRDX1, GDNF) and unmethylated gene body regions (SMOC1, DLL3) were observed in IDH-mutated tumors compared with wild-type. c Principal component analysis (PCA) of differentially methylated CpGs between 1p/19q-deleted and intact tumors identifying three CIMP groups (PPT 457 kb)

401_2013_1130_MOESM3_ESM.ppt

Supplementary Fig. S2 Chromosomal distribution of differentially methylated CpGs between a the CD-CIMP+, b the CIMP+ and c the CIMP− groups with respect to the controls (PPT 194 kb)

401_2013_1130_MOESM4_ESM.ppt

Supplementary Fig. S3 a Hierarchical clustering based on the 4,397 significant probes (corresponding to 2.210 genes) between the CD-CIMP+ and CIMP+ tumors (q < 0.05). Among these probes, 57.1 % of CpGs (2,508 probes; 1,227 genes) were methylated in CD-CIMP+, but unmethylated in CIMP+ tumors. Conversely, 42.9 % of the CpGs (1,889 probes; 1,102 genes) were methylated in the CIMP+ group and unmethylated in CD-CIMP+ tumors. b Genomic distribution and location relative to the CpG context of the differentially methylated CpGs between CD-CIMP+ and CIMP+ tumors (PPT 232 kb)

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Mur, P., Mollejo, M., Ruano, Y. et al. Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors. Acta Neuropathol 126, 277–289 (2013). https://doi.org/10.1007/s00401-013-1130-9

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  • DOI: https://doi.org/10.1007/s00401-013-1130-9

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