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Proc Natl Acad Sci U S A. 2017 Oct 3;114(40):10743-10748. doi: 10.1073/pnas.1708914114. Epub 2017 Sep 15.

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

Author information

1
Department of Neurological Surgery, University of California, San Francisco, CA 94158.
2
Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
3
Clark H. Smith Brain Tumor Center, Arnie Charbonneau Cancer Institute, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
4
Department of Radiology and Biomedical Imaging, University of California, San Francisco, CA 94158.
5
Department of Pathology, University of California, San Francisco, CA 94158.
6
Department of Neurosurgery, Henry Ford Health System, Detroit, MI 48202.
7
Department of Genetics, University of Sao Paulo, Ribeirao Preto, SP 14049-900, Brazil.
8
Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC V5Z 4S6, Canada.
9
Department of Medical Genetics, University of British Columbia, Vancouver, BC V5Z 4S6, Canada.
10
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA 94158.
11
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94158.
12
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94158.
13
Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; aluchman@ucalgary.ca joseph.costello@ucsf.edu.
14
Department of Neurological Surgery, University of California, San Francisco, CA 94158; aluchman@ucalgary.ca joseph.costello@ucsf.edu.

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.

KEYWORDS:

2HG; DNA methylation; IDH1; copy number; glioma

PMID:
28916733
PMCID:
PMC5635900
DOI:
10.1073/pnas.1708914114
[Indexed for MEDLINE]
Free PMC Article

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