A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence

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Summary: Glioma diagnosis is based on histomorphology and grading; however, such classification does not have predictive clinical outcome after glioblastomas have developed.To date, no bona fide biomarkers that significantly translate into a survival benefit to glioblastoma patients have been identified.We previously reported that the IDH mutant G-CIMP-high Calcium Carbonate subtype would be a predecessor to the G-CIMP-low subtype.

Here, we performed a comprehensive DNA methylation longitudinal analysis of diffuse gliomas from 77 patients (200 tumors) to enlighten the epigenome-based malignant transformation of initially lower-grade gliomas.Intra-subtype heterogeneity among G-CIMP-high primary tumors allowed us to identify predictive biomarkers for assessing the risk of malignant recurrence at early stages of disease.G-CIMP-low recurrence appeared in 9.

5% of all gliomas, and these resembled IDH-wild-type primary glioblastoma.G-CIMP-low recurrence can be characterized by distinct epigenetic changes at candidate functional tissue enhancers with AP-1/SOX binding elements, mesenchymal stem cell-like epigenomic phenotype, and genomic instability.Molecular abnormalities of longitudinal G-CIMP offer possibilities to defy glioblastoma progression.

: IDH-mutant lower-grade glioma glioblastoma often progresses to a more aggressive Wastebags phenotype upon recurrence.de Souza et al.examines the intra-subtype heterogeneity of initial G-CIMP-high and use this information to identify predictive biomarkers for assessing the risk of recurrence and malignant transformation.

Keywords: longitudinal gliomas, DNA methylation, IDH mutation, G-CIMP-high, intra-subtype heterogeneity, malignant transformation and recurrence, G-CIMP-low, stem cell-like glioblastoma, predictive biomarkers.