DELETION OR AMPLIFICATION OF MUTANT IDH1 IS ASSOCIATED WITH EXTREME DNA HYPOMETHYLATION AND MALIGNANT PROGRESSION

Mutations in IDH1 are the most common genetic alteration in low-grade gliomas (LGGs) and lead to overproduction of the oncometabolite 2-hydroxyglutarate (2HG) and altered DNA methylation (glioma CpG island methylator phenotype or G-CIMP). While mutant IDH1 likely initiates tumorigenesis, its role in tumor progression is less clear. We and others have previously found that mutations in IDH1 are maintained at recurrence, but several case reports have noted the loss of either the mutant or wild-type allele of IDH1 in vitro and in vivo. We therefore undertook a longitudinal analysis of copy number at the IDH1 locus in a cohort of 50 patients with IDH1-mutant LGG and patient-matched recurrences of all grades. We identified six cases (12%) in which the ratio of the mutant to wild-type allele was altered. Deletion or amplification of the mutant allele both coincided with malignant progression and resulted in decreased 2HG. While G-CIMP was uniformly maintained, there was extreme DNA hypomethylation outside CpG islands. The clonal expansion of tumor cells in the absence of mutant IDH1 and 2HG suggests that initially IDH1-mutant LGG can undergo malignant progression without mutant IDH1. These results have implications for therapeutic inhibition of mutant IDH1, and provide evidence that a driver of gliomagenesis may not be required for malignant progression in vivo.