Acta Neuropathologica

, Volume 126, Issue 2, pp 277–289 | Cite as

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

  • Pilar Mur
  • Manuela Mollejo
  • Yolanda Ruano
  • Ángel Rodríguez de Lope
  • Concepción Fiaño
  • Juan Fernando García
  • Javier S. Castresana
  • Aurelio Hernández-Laín
  • Juan A. Rey
  • Bárbara Meléndez
Original Paper

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.

Keywords

Methylation array Oligodendroglial tumors 1p/19q codeletion IDH mutation CIMP 

Supplementary material

401_2013_1130_MOESM1_ESM.xls (1017 kb)
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 (457 kb)
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 (194 kb)
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 (232 kb)
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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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Pilar Mur
    • 1
  • Manuela Mollejo
    • 1
    • 2
  • Yolanda Ruano
    • 3
  • Ángel Rodríguez de Lope
    • 4
  • Concepción Fiaño
    • 5
  • Juan Fernando García
    • 6
  • Javier S. Castresana
    • 7
  • Aurelio Hernández-Laín
    • 3
  • Juan A. Rey
    • 8
  • Bárbara Meléndez
    • 1
  1. 1.Molecular Pathology Research Unit, Department of PathologyVirgen de la Salud HospitalToledoSpain
  2. 2.Department of PathologyVirgen de la Salud HospitalToledoSpain
  3. 3.Department of Pathology (Neuropathology)12 de Octubre University HospitalMadridSpain
  4. 4.Department of NeurosurgeryPuerta del Hierro HospitalMadridSpain
  5. 5.Department of PathologyUniversity Hospital Complex of Vigo (C.H.U.V.I.)VigoSpain
  6. 6.Department of PathologyMD Anderson InternationalMadridSpain
  7. 7.Brain Tumor Biology UnitUniversity of Navarra School of SciencesPamplonaSpain
  8. 8.IdiPaz Research UnitLa Paz University HospitalMadridSpain

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