Abstract
ObjectiveTo identify novel epigenetic signatures that could provide predictive information that is complementary to promoter methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT) gene for predicting temozolomide (TMZ) response, among glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP)MethodsDifferent cohorts of primary non-G-CIMP GBMs with genome-wide DNA methylation microarray data were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different statistical analyses and functional experiments were performed for clinical and biological validation.ResultsBy employing discovery cohorts with radiotherapy (RT) and TMZ versus RT alone and a strict multistep selection strategy, we identified seven CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs with RT/TMZ, independent of age, MGMT promoter methylation status, and other identified CpGs. A RISK score signature of the 7 CpGs was developed and validated to distinguish non-G-CIMP GBMs with differential survival outcomes to RT/TMZ, but not to RT alone. The interaction analyses also showed differential outcomes to RT/TMZ versus RT alone within the RISK score-based subgroups. The signature could also improve the risk classification by age and MGMT promoter methylation status. Functional experiments showed that HSBP2 appeared to be epigenetically regulated by one identified CpG and was associated with TMZ resistance, but it was not associated with cell proliferation or apoptosis in GBM cell lines. The predictive value of the single CpG methylation of HSBP2 by pyrosequencing was observed in a local cohort of isocitrate dehydrogenase 1 (IDH1) R132H wild-type GBMs.ConclusionsThis novel epigenetic signature might be a promising predictive (but not a general prognostic) biomarker and be helpful for refining the MGMT-based guiding approach to TMZ usage in non-G-CIMP GBMs.
Highlights
Glioblastomas (GBMs) are a group of clinically refractory disease with apparent intertumor heterogeneity and a generally poor prognosis [1]
We investigated the major subgroup of GBMs that do not have the glioma-CpGs island methylator phenotype (G-CIMP), which is exclusively featured by the absence of isocitrate dehydrogenase (IDH) mutations [9]
Identification of a RISK score signature of seven CpGs with potential linkage to TMZ efficacy According to a strict selection strategy (Fig. 1a), we identified a panel of seven CpGs from the discovery cohorts (Table 1)
Summary
Glioblastomas (GBMs) are a group of clinically refractory disease with apparent intertumor heterogeneity and a generally poor prognosis [1]. Despite extensive explorations on novel therapeutic strategies such as anti-angiogenic therapy [2, 3], immunotherapy [4], and the use of tumor treating fields (TTFs) [5], the combination of radiotherapy (RT) and temozolomide (TMZ) had remained the standard adjuvant treatment for newly diagnosed GBMs [6]. The promoter methylation status of the O-6-methylguanine-DNA methyltransferase (MGMT), encoding a DNA repair enzyme that confers resistance to alkylating drugs, has been by far the most informative predictive biomarker for TMZ outcome in GBMs [7]. This single-gene methylation status has limitations for clinical utility, especially for guiding the choice of TMZ in unmethylated tumors [8]. Functional studies on this epigenetically regulated gene (HSBP2) provide additional biological and clinical insights to the multimarker signature
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