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

By: Camila Ferreirade SouzaThais S. SabedotTathiane M. MaltaLindsay StetsonOlena MorozovaArtem SokolovPeter W. LairdMaciej WiznerowiczAntonio IavaroneJames SnyderAnade CarvalhoZachary SanbornKerrie L. McDonaldWilliam A. FriedmanDaniela TirapelliLaila PoissonTom MikkelsenCarlos G. Carlotti Jr.Steven KalkanisJean ZenklusenSofie R. SalamaJill S. Barnholtz-SloanHoutan Noushmehr

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.

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Citation: de Souza CF, Sabedot TS, Malta TM, Stetson L, Morozova O, Sokolov A, Laird PW, Wiznerowicz M, Iavarone A, Snyder J, deCarvalho A, Sanborn Z, McDonald KL, Friedman WA, Tirapelli D, Poisson L, Mikkelsen T, Carlotti CG Jr, Kalkanis S, Zenklusen J, Salama SR, Barnholtz-Sloan JS, et al.; A Distinct DNA Methylation Shift in a Subset of Glioma CpG Island Methylator Phenotypes during Tumor Recurrence. Cell Rep. 2018 Apr 10;23(2):637-651. doi: 10.1016/j.celrep.2018.03.107. PMID:29642018