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Patient-derived models of IDH1-mutant, hypermutated glioma

Abstract

Gliomas are a group of central nervous system tumors that are classified based upon histopathological and molecular features. IDH-mutant low-grade gliomas (LGG) are prognostically favorable tumors and are often treated with temozolomide, but can undergo malignant progression via TMZ-induced hypermutation. Cell cultures that faithfully model this genetically distinct and clinically relevant hypermutated (HM) tumor subgroup are lacking, and are necessary to advance our understanding of HM tumors. We established patient-derived cell culture and xenograft models of HM oligodendroglioma and astrocytoma that faithfully recapitulate the molecular and functional features observed in their tumor of origin. We thoroughly characterized these cell lines and established that they are suitable for studying HM glioma, IDH-driven phenotypes, TERT promoter- and alternative lengthening of telomeres-driven cellular immortality, therapy-driven evolution, and intratumoral heterogeneity. These models have been widely shared with the neuro-oncology community and accelerated research at institutions across the United States.

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