期刊
CELL REPORTS
卷 23, 期 2, 页码 637-651出版社
CELL PRESS
DOI: 10.1016/j.celrep.2018.03.107
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资金
- Sao Paulo Research Foundation (FAPESP) [2016/15485-8, 2014/08321-3, 2015/07925-5, 2016/01975-3, 2014/02245-3, 2016/12329-5, 2016/06488-3, 2014/03989-6]
- Nucleo de Apoio a Pesquisa-Centro de Biologia Sistemica Integrada (NAP-CISBi) [12.1.17598.1.3]
- Department of Neurosurgery at Henry Ford Health System [A30935]
- Case Comprehensive Cancer Center Grants NIH/NCI [5P30CA043703, HHSN261201000057C]
- Foundation for Polish Science [2010/3-3]
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [16/01975-3, 16/15485-8, 14/08321-3, 16/06488-3] Funding Source: FAPESP
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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