Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant <i>IDH1</i>

Abstract

<i>IDH1</i> 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 <i>IDH1</i> mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the <i>IDH1</i> locus at recurrence. Deletion or amplification of <i>IDH1</i> was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from <i>IDH1</i> mutant, but not <i>IDH1</i> wild type, gliomas systematically deleted <i>IDH1</i> in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with <i>IDH1</i> CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while <i>IDH1</i> mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.