GENO-10: LOSS OF IDH MUTATION IN PATIENT-DERIVED BRAIN TUMOR INITIATING CELLS

Mutation of the IDH1 gene is found in virtually every grade II–III glioma and secondary GBM. IDH mutation is currently hypothesized as the initiating event leading to gliomagenesis, by maintaining an immature proliferative state in a common precursor cell of the astrocytic and oligodendroglial lineage, through epigenetic regulation. Our group has been working for several years to establish brain tumor initiating cell (BTIC) lines from IDH mutated gliomas. We find that IDH mutant BTICs, in addition to being refractory to in vitro culture conditions, systematically lose the IDH mutant phenotype via genetic alterations of chromosome 2, which leads to the loss of either the IDH wild type or mutant allele. Furthermore, we also observed gradual loss of chromosome 2 and IDH mutation in vivo, in a serial orthotopic xenograft model of patient-derived glioma cells. Of note, disappearance, at recurrence, of a pre-existing IDH mutation has been reported in the literature. We confirm the loss of IDH mutation and show that various chromosome 2 alterations affecting the IDH1 locus arise in a subset of cells that are being selected both in vitro and in vivo, suggesting proliferation/survival advantages. Based on our observations, we propose that even though the IDH mutation is essential for tumor initiation, it may be dispensable once a durable transformed state is acquired through the acquisition of additional mutations. The loss of IDH mutation not only represents a potential mechanism of resistance to future IDH mutant-specific therapies, but also raises the intriguing possibility that such therapeutic strategies may increase the selection pressure against the IDH mutation and may eventually lead to a more aggressive phenotype. A larger study focusing on the loss of the IDH mutation in the clinic, at recurrence, will be essential to evaluate the frequency and clinical relevance of this phenomenon.