Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1

Author(s):Show less -

Mazor, Tali ^[1] ; Chesnelong, Charles ^{[2, 3]} ; Pankov, Aleksandr ^[1] ; Jalbert, Llewellyn E. ^[4] ; Hong, Chibo ^[1] ; Hayes, Josie ^[1] ; Smirnov, Ivan V. ^[1] ; Marshall, Roxanne ^[5] ; Souza, Camila F. ^{[6, 7]} ; Shen, Yaoqing ^[8] ; Viswanath, Pavithra ^[4] ; Noushmehr, Houtan ^{[6, 7]} ; Ronen, Sabrina M. ^[4] ; Jones, Steven J. M. ^{[8, 9]} ; Marra, Marco A. ^{[8, 9]} ; Cairncross, J. Gregory ^[3] ; Perry, Arie ^{[1, 5]} ; Nelson, Sarah J. ^{[4, 10]} ; Chang, Susan M. ^[1] ; Bollen, Andrew W. ^[5] ; Molinaro, Annette M. ^{[11, 1]} ; Bengtsson, Henrik ^{[11, 12]} ; Olshen, Adam B. ^{[11, 12]} ; Weiss, Samuel ^{[2, 3]} ; Phillips, Joanna J. ^{[1, 5]} ; Luchman, H. Artee ^{[2, 3]} ; Costello, Joseph F. ^[1]

Affiliation:Show less -

^[1] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 - USA

^[2] Univ Calgary, Cumming Sch Med, Dept Cell Biol & Anat, Hotchkiss Brain Inst, Calgary, AB T2N 4N1 - Canada

^[3] Univ Calgary, Cumming Sch Med, Dept Clin Neurosci, Clark H Smith Brain Tumor Ctr, Arnie Charbonneau C, Calgary, AB T2N 4N1 - Canada

^[4] Univ Calif San Francisco, Dept Radiol & Biomed Imaging, San Francisco, CA 94158 - USA

^[5] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 - USA

^[6] Univ Sao Paulo, Dept Genet, BR-14049900 Ribeirao Preto, SP - Brazil

^[7] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 - USA

^[8] British Columbia Canc Agcy, Canadas Michael Smith Genome Sci Ctr, Vancouver, BC V5Z 4S6 - Canada

^[9] Univ British Columbia, Dept Med Genet, Vancouver, BC V5Z 4S6 - Canada

^[10] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94158 - USA

^[11] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94158 - USA

^[12] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 - USA

• Document type: Journal article
• Source: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 114, n. 40, p. 10743-10748, OCT 3 2017.
• Web of Science Citations: 33

Abstract

IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite D-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions. (AU)

• 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: 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: 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