Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis

Abstract

Extensive genomic and gene expression studies have been performed in gliomas, but the epigenetic alterations that characterize different subtypes of gliomas remain largely unknown. Here, we analyzed the methylation patterns of 807 genes (1536 CpGs) in a series of 33 low-grade gliomas (LGGs), 36 glioblastomas (GBMs), 8 paired initial and recurrent gliomas, and 9 controls. This analysis was performed with Illumina's Golden Gate Bead methylation arrays and was correlated with clinical, histological, genomic, gene expression, and genotyping data, including IDH1 mutations. Unsupervised hierarchical clustering resulted in 2 groups of gliomas: a group corresponding to de novo GBMs and a group consisting of LGGs, recurrent anaplastic gliomas, and secondary GBMs. When compared with de novo GBMs and controls, this latter group was characterized by a very high frequency of IDH1 mutations and by a hypermethylated profile similar to the recently described glioma CpG island methylator phenotype. MGMT methylation was more frequent in this group. Among the LGG cluster, 1p19q codeleted LGG displayed a distinct methylation profile. A study of paired initial and recurrent gliomas demonstrated that methylation profiles were remarkably stable across glioma evolution, even during anaplastic transformation, suggesting that epigenetic alterations occur early during gliomagenesis. Using the Cancer Genome Atlas data set, we demonstrated that GBM samples that had an LGG-like hypermethylated profile had a high rate of IDH1 mutations and a better outcome. Finally, we identified several hypermethylated and downregulated genes that may be associated with LGG and GBM oncogenesis, LGG oncogenesis, 1p19q codeleted LGG oncogenesis, and GBM oncogenesis.

A Hypermethylated Phenotype Is a Better Predictor of Survival than MGMT Methylation in Anaplastic Oligodendroglial Brain Tumors: A Report from EORTC Study 26951

“…Other prognostic markers in gliomas include 1p19q LOH (27), IDH1 mutation status (6,28,29), and MGMT methylation status (3,6,28) or whole-genome approaches such as gene expression profiling (20,25,26,30) and, similar to reported in this study, methylation profiling (13)(14)(15). These prognostic markers may help classify gliomas as histologic classification is troublesome and subject to interobserver variation (31)(32)(33)(34).…”

“…13). Later studies showed that histologic subtype was associated with methylation class and IDH1 mutation, and that GBMs generally show less overall CpG methylation than lower grade gliomas (14,15). Identification of CpG methylation sites in gliomas may therefore identify genes involved in the initiation and/or progression of gliomas [see e.g., (16,17)].…”

A heterozygous IDH1R132H/WT mutation induces genome-wide alterations in DNA methylation

“…RBP1 has been demonstrated to be one of the genes most frequently subject to epigenetic silencing in G-CIMP+ primary GBMs (Noushmehr et al 2010;Laffaire et al 2011) and was also among the most strikingly subject to concordant hypermethylation and down-regulation in our model. In addition to gliomas, RBP1 is also silenced in conjunction with promoter hypermethylation in several cancer types, including lymphomas, esophageal squamous cell carcinomas, and gastric carcinomas (Esteller et al 2002;Mizuiri et al 2005;Shutoh et al 2005;Chu et al 2006).…”

“…A subset of primary GBMs exhibit the ''CpG island methylator phenotype'' (CIMP) and show concordant hypermethylation of a large number of CpG islands Noushmehr et al 2010). Interestingly, in gliomas, the CIMP phenotype (termed G-CIMP) has a striking association with IDH1 mutation (Noushmehr et al 2010;Christensen et al 2011;Laffaire et al 2011;Turcan et al 2012). Similarly, IDH1 and IDH2 mutations robustly associate with specific global DNA hypermethylation phenotypes in AMLs (Figueroa et al 2010a), enchondromas (Pansuriya et al 2011), and low-grade gliomas (LGGs) .…”

Identification of TET1 Partners That Control Its DNA-Demethylating Function

“…10,13,14 According to this hypothesis, we focused our analysis on 3 genes frequently hypomethylated in GBM (i.e., the MMP2, SH3BP2, and Serpine1 genes) and on 9 genes frequently hypermethylated in GBM (i.e., the AHR, CD81, DIO3, FZD9, HTR1B, HCK, IRAK3, PRKCDBP, and TUSC3 genes) (Fig. 4A).…”