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

Citation:

Camila Ferreira de Souza, Thais S Sabedot, Tathiane M Malta, Lindsay Stetson, Olena Morozova, Artem Sokolov, Peter W Laird, Maciej Wiznerowicz, Antonio Iavarone, James Snyder, Ana deCarvalho, Zachary Sanborn, Kerrie L McDonald, William A Friedman, Daniela Tirapelli, Laila Poisson, Tom Mikkelsen, Carlos G Carlotti, Steven Kalkanis, Jean Zenklusen, Sofie R Salama, Jill S Barnholtz-Sloan, and Houtan Noushmehr. 2018. “A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence.” Cell Rep, 23, 2, Pp. 637-651.

Abstract:

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.