Spatial concordance of DNA methylation classification in diffuse glioma

Abstract

Background Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. Methods We used neuronavigation to acquire 133 image-guided and spatially-separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast enhanced T1 weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a three-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. Results Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. Conclusion Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response

“…We next asked whether epigenetic diversity accelerates tumor evolution by promoting cell survival in resource-deprived tumor environments (e.g., hypoxia or therapeutic exposures). To address this question and extend the generalizability of our findings, we analyzed DNAme profiles from large-scale microarray-based bulk glioma studies 2 , 4 , 52 . We inferred a microarray metric from the single-cell DNAme data that quantified the DNAme disorder-susceptible gene regions ( Figure 7a ).…”

“…We next applied the bulk DNAme disorder metric to 119 image-guided stereotactic biopsies taken from spatially distinct regions across IDH-wild-type ( n =57 biopsies, 6 patients) and IDH-mutant ( n =62 biopsies, n =8 patients) tumors 52 . This quantified the physical distance between each sample and the tumor’s center, based on specific radiographic features (e.g., magnetic resonance imaging contrast-enhanced region,).…”

“…Data re-analysis of longitudinal glioma resources was accessed for Klughammer et al ( http://www.medical-epigenomics.org/papers/GBMatch/ ) 5 and the Glioma Longitudinal AnalySiS consortium (GLASS, http://synapse.org/glass ) 4 . Magnetic Resonance Imaging guided biopsies taken from spatially distinct regions and subjected to bulk DNAme Illumina methylation microarray collected by our group was also accessed EGAS00001005434 52 . DNAme microarrays (450K) were also retrieved The Cancer Genome Atlas initial glioma samples 2 .…”

CpG Island Methylator Phenotype—A Hope for the Future or a Road to Nowhere?

“…A clear example of such a molecular sequence comes from the field of colorectal cancer. For example, a 2006 study of serrated polyps and colon adenomas showed that CIMP develops early, whereas MSI develops late in serrated polyps/adenoma-carcinoma sequence [115]. Consequently, recent 3-year surveillance of small colorectal polyps has demonstrated the presence of CIMP in 32% of samples while none of the polyps displayed MSI [116].…”

“…Recent studies explored CIMP in the context of spatial tumour heterogeneity. Verburg et al applied methylation profiling of multiple sections of diffuse glioma from 16 patients and found only little spatial heterogeneity within each tumour [115]. Similarly, Flatin et al investigated CIMP in two to four multiregional samples from 30 colorectal primary tumours and found that CIMP status was consistent between multiregional samples.…”