Murine modeling of IDH-mutant 1p/19q-codeleted oligodendroglioma reveals genotype specific phenotypes.

Abstract

Background: Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. A lack of faithful preclinical model systems for this disease has limited progress in understanding the biology of this genetically unique subtype of adult diffuse-type glioma and in developing new effective therapies. To address this unmet need, we sought to establish a mouse model that faithfully recapitulates the genetic and phenotypic features of human IDH-mutant 1p/19q-codeleted oligodendroglioma.

Methods: We performed in utero electroporation to introduce distinct combinations of genetic alterations and evaluated their potential to form tumors. Resulting tumors were characterized by histology, metabolite profiling, RNA-sequencing and single-cell RNA sequencing.

Results: We identified co-expression of IDH1R132H and PIK3CAE545K together with loss of Cic, Fubp1 and Cdkn2a (termed OligoCdkn2a) as the optimal genetic combination to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant 1p/19q-codeleted oligodendroglioma. Substituting Cdkn2a loss with Trp53 deletion decreased latency and shifted tumors toward high-grade astrocytoma histology. OligoCdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single-cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model.

Conclusions: To our knowledge, OligoCdkn2a tumors represent the first autochthonous, genetically engineered mouse model to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas. This model will provide a valuable platform to further dissect mechanisms of tumorigenesis and test novel therapeutic strategies for this molecularly distinct glioma subtype.