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

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.

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Dataset ID Description Technology Samples
EGAD00001003763 15
EGAD00001003764 4
EGAD00010001408 Illumina 450K 34
Publications Citations
Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant <i>IDH1</i>.
Proc Natl Acad Sci U S A 114: 2017 10743-10748
Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas.
Clin Cancer Res 25: 2019 747-759
MGMT promoter methylation level in newly diagnosed low-grade glioma is a predictor of hypermutation at recurrence.
Neuro Oncol 22: 2020 1580-1590
Haploinsufficiency of NFKBIA reshapes the epigenome antipodal to the IDH mutation and imparts disease fate in diffuse gliomas.
Cell Rep Med 4: 2023 101082