Genome stability is crucial for normal mammalian development. Broadly, genome maintenance is carried out by two distinct mechanisms; functional integration of DNA replication and DNA damage response signaling. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects to the nervous system, including neurodegenerative disease and cancer. It remains unclear which DNA repair pathways are critical for preventing DNA damage accumulation in stem and progenitor cells. The same mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of the current study is delineation of key factors for genome stability that prevent tumorigenesis during cortical neurogenesis. We have compared the differential effects of inactivation of homologous recombination (HR) and non-homologous end-joining (NHEJ) towards tumorigenesis by directing their deletion specifically to early cortical progenitors in mouse models. We recently found that coincident loss of either of these repair pathways result in high-grade glioma formation. Furthermore, modelling histone H3 mutations found in human high-grade glioma, specifically the H3.3 K27M mutation, we found that gliomagenesis was accelerated after defective HR (Brca2 loss) or NHEJ (Lig4 loss), although the resultant cancers showed distinct differences in penetrance and diffusion throughout the cortex. Interestingly, gliomas resulting from NHEJ inhibition were more penetrant and diffuse than brain tumors subsequent from HR loss. Gene expression analysis through RNA sequencing is currently being used to identify causative events that drive these individual tumor identities. Embryonic analysis has further shown that inhibition of these repair pathways in combination with the H3.3 K27M mutation results in distinct spatiotemporal DNA damage early in cortical development. Our recent discoveries support cortical progenitor susceptibility to genomic damage is not only influenced by a critical early period of development but also the suppression of specific tumorigenic mutations involving DNA damage repair pathways and histone modifications during neurogenesis.

Citation Format: Lee J. Pribyl, Susanna M. Downing, Cristel V. Camacho, Jon D. Larson, Suzanne J. Baker, Peter J. McKinnon. Genomic instability and the development of high-grade gliomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-289.