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Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification.

ABSTRACT: BACKGROUND:A feature of glioblastoma (GBM) is cellular and molecular heterogeneity, both within and between tumors. This variability causes a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous intratumor gene expression in GBM is well documented, but little is known regarding the epigenetic heterogeneity. Variability in DNA methylation within tumors would have implications for diagnostics, as methylation can be used for tumor classification, subtyping, and determination of the clinically used biomarker O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. We therefore aimed to profile the intratumor DNA methylation heterogeneity in GBM and its effect on diagnostic properties. METHODS:Three to 4 spatially separated biopsies per tumor were collected from 12 GBM patients. We performed genome-wide DNA methylation analysis and investigated intratumor variation. RESULTS:All samples were classified as GBM isocitrate dehydrogenase (IDH) wild type (wt)/mutated by methylation profiling, but the subclass differed within 5 tumors. Some GBM samples exhibited higher DNA methylation differences within tumors than between, and many cytosine-phosphate-guanine (CpG) sites (mean: 17?000) had different methylation levels within the tumors. MGMT methylation status differed in IDH mutated patients (1/1). CONCLUSIONS:We demonstrated that intratumor DNA methylation heterogeneity is a feature of GBM. Although all biopsies were classified as GBM IDH wt/mutated by methylation analysis, the assigned subclass differed in samples from the same patient. The observed heterogeneity within tumors is important to consider for methylation-based biomarkers and future improvements in stratification of GBM patients.

SUBMITTER: Wenger A

PROVIDER: S-EPMC6502500 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification.

Wenger Anna A Ferreyra Vega Sandra S Kling Teresia T Bontell Thomas Olsson TO Jakola Asgeir Store AS Carén Helena H

Neuro-oncology 20190501 5

<h4>Background</h4>A feature of glioblastoma (GBM) is cellular and molecular heterogeneity, both within and between tumors. This variability causes a risk for sampling bias and potential tumor escape from future targeted therapy. Heterogeneous intratumor gene expression in GBM is well documented, but little is known regarding the epigenetic heterogeneity. Variability in DNA methylation within tumors would have implications for diagnostics, as methylation can be used for tumor classification, sub ...[more]

PMID: 30668814

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Project description:BackgroundEpendymal tumors are glial tumors that commonly manifest in children and young adults. Their classification has remained entirely morphological until recently, and surgery and radiotherapy are the main treatment options, especially in adults. Here we sought to correlate DNA methylation profiles with clinical and pathological characteristics in the prospective cohort of the German Glioma Network.MethodsTumors from 122 adult patients with myxopapillary ependymoma, ependymoma, anaplastic ependymoma, subependymoma, or RELA fusion-positive ependymoma classified according to the World Health Organization (WHO) 2016 were subjected to DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform. Molecular data were correlated with histologic features and clinical characteristics.ResultsAt a median follow-up of 86.7 months, only 22 patients experienced progression (18.0%) and 13 patients (10.7%) died. Each tumor could be assigned to one of the previously defined molecular ependymoma subgroups. All histologic subependymomas corresponded to subependymoma (SE) DNA methylation subgroups, but the reverse was not true: 19 histologic ependymomas (WHO grade II) were allocated to molecular SE groups. Similarly, all histological myxopapillary ependymomas were assigned to the molecularly defined spinal myxopapillary ependymoma (SP-MPE) class, but this molecular subgroup additionally included 15 WHO grade II ependymomas by histology. Overall, WHO grade II ependymomas distributed into 7 molecular subgroups.ConclusionMost adult patients with ependymoma show a favorable prognosis. Molecular classification may provide diagnostic and prognostic information beyond histology and facilitate patient stratification in future clinical trials. The prognostic significance of a subependymoma or myxopapillary ependymoma DNA methylation phenotype without corresponding histology requires further study.Key points1. Ependymoma diagnosed in adult patients most often shows a good prognosis. 2. Molecular classification can support diagnostic and prognostic information beyond histology.

Dataset Information

Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification.

Publications

Intratumor DNA methylation heterogeneity in glioblastoma: implications for DNA methylation-based classification.

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