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

Author(s):Show less -

de Souza, Camila Ferreira ^{[1, 2]} ; Sabedot, Thais S. ^{[1, 2]} ; Malta, Tathiane M. ^{[1, 2]} ; Stetson, Lindsay ^[3] ; Morozova, Olena ^{[4, 5]} ; Sokolov, Artem ^[6] ; Laird, Peter W. ^[7] ; Wiznerowicz, Maciej ^{[8, 9, 10]} ; Iavarone, Antonio ^{[11, 12]} ; Snyder, James ^[2] ; deCarvalho, Ana ^[2] ; Sanborn, Zachary ^[13] ; McDonald, Kerrie L. ^[14] ; Friedman, William A. ^[15] ; Tirapelli, Daniela ^[16] ; Poisson, Laila ^{[2, 17]} ; Mikkelsen, Tom ^[2] ; Carlotti, Jr., Carlos G. ^[16] ; Kalkanis, Steven ^[2] ; Zenklusen, Jean ^[18] ; Salama, Sofie R. ^{[4, 5]} ; Barnholtz-Sloan, Jill S. ^[3] ; Noushmehr, Houtan ^{[1, 2]}

Affiliation:Show less -

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP - Brazil

^[2] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 - USA

^[3] Case Western Reserve Univ, Sch Med, Case Comprehens Canc Ctr, Cleveland, OH 44106 - USA

^[4] Univ Calif Santa Cruz, UC Santa Cruz Genom Inst, Santa Cruz, CA 95064 - USA

^[5] Univ Calif Santa Cruz, Howard Hughes Med Inst, Santa Cruz, CA 95064 - USA

^[6] Harvard Med Sch, Lab Syst Pharmacol, Boston, MA 02115 - USA

^[7] Van Andel Res Inst, Ctr Epigenet, Grand Rapids, MI 49503 - USA

^[8] Greater Poland Canc Ctr, Dept Diagnost & Canc Immunol, Lab Gene Therapy, Poznan - Poland

^[9] Poznan Univ Med Sci, Dept Canc Immunol, Poznan - Poland

^[10] Int Inst Mol Oncol, Poznan - Poland

^[11] Columbia Univ, Dept Pathol & Cell Biol, New York, NY 10032 - USA

^[12] Columbia Univ, Neurol Inst Canc Genet, New York, NY 10032 - USA

^[13] NantOmics LLC, Santa Cruz, CA - USA

^[14] UNSW, Prince Wales Clin Sch, Cure Brain Canc Biomarkers & Translat Res Lab, Sydney, NSW - Australia

^[15] Univ Florida, Dept Neurosurg, Gainesville, FL - USA

^[16] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Surg & Anat, Ribeirao Preto - Brazil

^[17] Henry Ford Hlth Syst, Dept Publ Hlth Sci, Detroit, MI 48202 - USA

^[18] NCI, Bethesda, MD 20892 - USA

• Document type: Journal article
• Source: CELL REPORTS; v. 23, n. 2, p. 637-651, APR 10 2018.
• Web of Science Citations: 21

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. (AU)

• FAPESP's process: 14/03989-6 - Uncovering pathophysiological and molecular mechanisms involved in tumorigenesis by platforms for next-generation sequencing (NGS)
• Grantee: Margaret de Castro
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 16/15485-8 - Clinical biomarkers in central nervous system tumors
• Grantee: Camila Ferreira de Souza
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 16/06488-3 - Integrative epigenomic analysis of high and low Glioma-CpG island Methylator Phenotype (G-CIMP): characterization and methods development
• Grantee: Thaís Sarraf Sabedot
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 14/08321-3 - Identification and characterization of functional genomic elements associated with progression of low to high grade glioma: integrative study of genome and epigenome
• Grantee: Camila Ferreira de Souza
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 16/12329-5 - Chromatin accessibility and DNA methylation changes associated with high and low Glioma-CpG island methylator phenotype (G-CIMP)
• Grantee: Thaís Sarraf Sabedot
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• FAPESP's process: 16/01975-3 - Defining stem cell epigenomic signatures in 33 different tumor types across 9000+ tumor samples
• Grantee: Tathiane Maistro Malta Pereira
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• FAPESP's process: 14/02245-3 - Identification of epigenomic signatures that define open chromatin regulatory networks associated with mesenchymal differentiation from human pluripotent stem cells
• Grantee: Tathiane Maistro Malta Pereira
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/07925-5 - Open source software statistical tools to aid in analyzing and integrating large cancer epigenomic datasets in order to decipher and understand regulatory networks
• Grantee: Houtan Noushmehr
• Support Opportunities: Research Grants - Young Investigators Grants