P19.02.A FUNCTIONAL CONSEQUENCES OF IDH1 AND CIC MUTATIONS ON OLIGODENDROGLIOMA CELLS OF ORIGIN

Abstract

Abstract BACKGROUND Oligodendrogliomas are primitive tumors of the central nervous system characterized by mutations in isocitrate dehydrogenase 1 (IDH1R132H) gene, codeletion of 1p and 19q chromosomic arms and mutations in Capicua (CIC) gene. Oligodendrocyte precursor cells (OPCs) are potential cells of origin for oligodendrogliomas and OPC-like tumor cells are responsible for tumor amplification at early stages of gliomagenesis. Although genetic alterations are well characterized for these tumors, little is known about the roles of IDH1 and CIC in oligodendroglioma initiation and development. Individually, IDH1 and CIC mutations can induce neoplastic characteristics but are not sufficient for tumoral development. We aim to understand how IDH1 and CIC mutations impact OPC development and whether these alterations are sufficient for tumoral initiation. METHODS We have generated an inducible mouse model allowing endogenous expression of IDH1R132H and inactivation of CIC in postnatal OPCs. We analyzed by immunofluorescence the proliferation and differentiation status of mutated oligodendroglial cells and other brain cells, at postnatal and adult stages. RESULTS We describe distinct effects of these mutations on oligodendroglial cell number and proliferation, at early and late time points. In addition, we found that IDH1R132H increases the proliferation of other brain cell types, suggesting paracrine effects of this mutation in the brain. We find no evidence of tumor in the brain of mice mutated for both IDH1 and CIC at late time points. CONCLUSION Our study describes for the first time the phenotypic impact of the combined expression of IDH1 and CIC mutations on oligodendroglial lineage cells and other brain cells, leading to a better understanding of oligodendroglioma development.