Histomorphology and current grading schemes are unable to predict glioma relapse and malignant tumor progression. We reported that the IDH-mutant associated Glioma-CpG Island Methylator Phenotype (G-CIMP) can be further divided into two clinically distinct subtypes independent of histopathological grading (G-CIMP-high and -low) with evidence of correlation with tumor progression. Here we performed a comprehensive epigenomic analysis of 74 longitudinally collected glioma samples (grade II-IV) to understand malignant recurrence from G-CIMP-high to G-CIMP-low. G-CIMP-low recurrence appeared in 12% of all gliomas and resemble IDH-wildtype primary glioblastoma. G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, stem cell-like epigenomic phenotype, and genomic instability. Finally, we defined a set of candidate biomarker signatures that predict recurrence of G-CIMP-low with clinically relevance on patient outcomes. Our study provides opportunity for refined clinical trial designs and therapeutic targets that limit progression to more aggressive G-CIMP-low phenotype.

Distinct epigenetic shift in a subset of Glioma CpG island methylator phenotype (G-CIMP) during tumor recurrence