DNA methylation signatures for 2016 WHO classification subtypes of diffuse gliomas

Abstract

BackgroundGlioma is the most common of all primary brain tumors with poor prognosis and high mortality. The 2016 World Health Organization classification of the tumors of central nervous system uses molecular parameters in addition to histology to redefine many tumor entities. The new classification scheme divides diffuse gliomas into low-grade glioma (LGG) and glioblastoma (GBM) as per histology. LGGs are further divided into isocitrate dehydrogenase (IDH) wild type or mutant, which is further classified into either oligodendroglioma that harbors 1p/19q codeletion or diffuse astrocytoma that has an intact 1p/19q loci but enriched for ATRX loss and TP53 mutation. GBMs are divided into IDH wild type that corresponds to primary or de novo GBMs and IDH mutant that corresponds to secondary or progressive GBMs. To make the 2016 WHO subtypes of diffuse gliomas more robust, we carried out Prediction Analysis of Microarrays (PAM) to develop DNA methylation signatures for these subtypes.ResultsIn this study, we applied PAM on a training set of diffuse gliomas derived from The Cancer Genome Atlas (TCGA) and identified DNA methylation signatures to classify LGG IDH wild type from LGG IDH mutant, LGG IDH mutant with 1p/19q codeletion from LGG IDH mutant with intact 1p/19q loci and GBM IDH wild type from GBM IDH mutant with an accuracy of 99–100%. The signatures were validated using the test set of diffuse glioma samples derived from TCGA with an accuracy of 96 to 99%. In addition, we also carried out additional validation of all three signatures using independent LGG and GBM cohorts. Further, the methylation signatures identified a fraction of samples as discordant, which were found to have molecular and clinical features typical of the subtype as identified by methylation signatures.ConclusionsThus, we identified methylation signatures that classified different subtypes of diffuse glioma accurately and propose that these signatures could complement 2016 WHO classification scheme of diffuse glioma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-017-0331-9) contains supplementary material, which is available to authorized users.

Integrating multiple‐level molecular data to infer the distinctions between glioblastoma and lower‐grade glioma

“…suggested that there were some differential long noncoding RNAs (lncRNAs) between GBMs and LGGs. Paul et al . utilized DNA methylation signatures to accurately classify different subtypes of diffuse gliomas.…”

“…9 Reon et al 10 suggested that there were some differential long noncoding RNAs (lncRNAs) between GBMs and LGGs. Paul et al 11 utilized DNA methylation signatures to accurately classify different subtypes of diffuse gliomas. However, the distinguishing effects were barely satisfactory given the complexity of brain tumors.…”

Therapeutic Targeting of Cancer Stem Cells in Human Glioblastoma by Manipulating the Renin-angiotensin System

“…IDHwildtype GB tends to arise de novo, while IDH-mutants tend to progress from lower-grade precursor lesions and are commonly found in younger patients (Nobusawa, Watanabe et al 2009). IDH mutants with methylation fingerprints (Paul, Mondal et al 2017) are associated with a better survival rate due to the accumulation of 2-hydroxyglutarate, secondary to loss of normal enzymatic function (Fathi, Nahed et al 2016), increasing the sensitivity of the tumors to selective chemoradiotherapy (van den Bent, Weller et al 2017). Genetic alterations typical of IDH-wildtype GB include TERT promoter mutations (80%), loss of chromosome 10q (70%), homozygous deletion of CDKN2A/DKN2B (60%), loss of chromosome 10p (50%), EGFR alterations (55%), PTEN mutations (40%), TP53 mutations (25-30%), and PI3K mutations (25%) (Louis, Perry et al 2016).…”

Differential mRNA and miRNA expression in oligodendrogliomas of different grades of malignancy

“…This has been supported by recent study that epigenetic signatures may further compliment the diagnosis of diffuse gliomas [25]. In pertinent to diffuse gliomas, a recent study by Paul and colleagues proposes that the identification of methylation signatures could potentially complement WHO-2016 classification scheme of different subtypes of diffuse glioma [26]. The methylation status is also true for oligodendrogliomas that will be discussed in later sections (and figure 3).…”

“…Identification of epigenetic i.e. methylation signatures may further compliment the patient outcome [25,26]. Subsequently, Mainz et al, showed that low-grade mixed oligoastrocytoma exhibit either characteristic astrocytic lesions (TP53 mutations) or combined loss of 1p/19q, pointing out that at the molecular level mixed tumours do not exist [114].…”