Despite advances in modern neuro-oncology, glioblastoma (GBM) continues to have a poor prognosis. Survival rates of adult GBM patients in the United States are quite low with 1-year, 2-year, 3-year, and 5-year relative survival rates estimated at 39.3, 16.9, 9.9, and 5.5%, respectively [
26]. While the majority of GBM patients live no longer than 2 years, there is a subset of patients who live longer than 3 years and are classified as long-term survivors (LTS). This group of patients remains a puzzle to researchers in the field, as studies on clinical, radiological, histological, and molecular characteristics have yet to yield consensus regarding determinants of durable response to the current treatment [
2,
3,
12,
14,
15,
20,
22,
24,
28,
29,
35‐
37]. For example, efforts to identify specific gene expression profiling patterns for LTS-GBM failed to uncover consistent features [
8,
9,
30]. The classic genetic markers of favorable prognosis of GBM such as
O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation or
isocitrate dehydrogenase (IDH) mutation do not fully account for long term survivors of glioblastoma (LTS-GBM) [
1,
9,
10,
21,
33,
39]. In particular, there are few studies for identification of molecular features associated with glioblastoma independent from
IDH mutation or the
IDH mutation-related signatures such as DNA methylation pattern called ‘Glioma CpG Island Hypermethylator Phenotype (G-CIMP)’ [
8]. Although there is a report of concurrent gain of chromosomes 19 and 20 as a favorable prognostic factor for a subset of LTS-GBM that did not show G-CIMP, multiple other studies revealed no distinctive DNA copy number changes in LTS-GBM [
9,
10,
30]. These results suggest that there is little chance to define LTS-GBM with a single genetic or epigenetic mechanism, emphasizing the importance of integrative understanding of molecular signatures in LTS-GBM. In fact, a recent integrated genomic analysis comparing LTS and short-term survivors (STS) GBM showed that multiple genetic and epigenetic factors are involved in divergent molecular features between the two extremes of the survival spectrum [
28].
Although there have been some genome-wide studies for DNA methylation in survival outliers of brain cancer, most of them have largely focused on promoter regions and CpG islands (CGIs) in identifying aberrant methylation patterns or in classifying GBM due to its readiness of biological interpretation in terms of transcriptional regulation [
16,
44]. However, the DNA methylation outside promotor-associated CGIs presents distinctive signatures in tumors and has significant effects on oncogenic pathways through multiple mechanisms. For example, DNA methylation of the CpG sites in gene body is known to be a major cause of cytosine to thymine transition mutations, as well as known to stimulate transcription elongation [
11]. Moreover, there is a genome-wide crosstalk, not limited to genic region, between DNA methylation and histone modifications [
19,
32]. One good example is that trimethylation of histone H3 lysine 9 (H3K9me3) is required for
DNMT3B dependent de novo DNA methylation [
32]. Therefore, unbiased analysis of DNA methylation across the whole genome is necessary to perform an integrative analysis of GBM of exceptional clinical course.