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

Significance Identifying the drivers of tumorigenesis provides insight into mechanisms of transformation and can suggest novel therapeutic targets. IDH1 mutations in gliomas are one such promising target. Drivers of tumor initiation may be distinct from those at tumor recurrence, however. Here, we demonstrate that in a subset of initially IDH1 mutant gliomas IDH1 is deleted or amplified at recurrence, yielding a higher grade tumor with a reprogrammed epigenome. We also report systematic selection for cells with IDH1 CNA in vitro and in vivo. Thus, while IDH1 mutation likely initiates gliomagenesis, neither mutant IDH1 nor the oncometabolite 2HG that it produces are required at recurrence. These findings have important implications for emerging therapeutic strategies targeting 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.