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

• Published in: Cell reports (Cambridge) Vol. 23; no. 2; pp. 637 - 651
• Main Authors: de Souza, Camila Ferreira, Sabedot, Thais S., Malta, Tathiane M., Stetson, Lindsay, Morozova, Olena, Sokolov, Artem, Laird, Peter W., Wiznerowicz, Maciej, Iavarone, Antonio, Snyder, James, deCarvalho, Ana, Sanborn, Zachary, McDonald, Kerrie L., Friedman, William A., Tirapelli, Daniela, Poisson, Laila, Mikkelsen, Tom, Carlotti, Carlos G., Kalkanis, Steven, Zenklusen, Jean, Salama, Sofie R., Barnholtz-Sloan, Jill S., Noushmehr, Houtan
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.04.2018; Elsevier
• Subjects: Adult; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Brain Neoplasms - genetics; Brain Neoplasms - mortality; Brain Neoplasms - pathology; Brain Neoplasms - therapy; CpG Islands; DNA Methylation; Female; G-CIMP-high; G-CIMP-low; Genomic Instability; Glioma - genetics; Glioma - mortality; Glioma - pathology; Glioma - therapy; Humans; IDH mutation; intra-subtype heterogeneity; Isocitrate Dehydrogenase - genetics; Kaplan-Meier Estimate; longitudinal gliomas; Longitudinal Studies; Male; malignant transformation and recurrence; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Recurrence, Local - genetics; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - metabolism; Phenotype; predictive biomarkers; Prognosis; stem cell-like glioblastoma; intra-subtype heterogeneity; predictive biomarkers; G-CIMP-high; malignant transformation and recurrence; longitudinal gliomas; DNA methylation; G-CIMP-low; IDH mutation; stem cell-like glioblastoma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2018.03.107

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 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. [Display omitted] •Intra-subtype heterogeneity of initially G-CIMP-high carries worst prognosis•G-CIMP-low is defined by DNA signature motifs for STAT3 and c-JUN/AP-1 at recurrence•G-CIMP-low at recurrence mimics an IDH-wild-type and stem cell-like primary GBM•Predictive biomarkers of glioma malignant transformation and recurrence are observed at diagnosis IDH-mutant lower-grade glioma glioblastoma often progresses to a more aggressive 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.