Simultaneous Nbs1 and p53 inactivation in neural progenitors triggers High‐Grade Gliomas (HGG)

Nijmegen Breakage Syndrome (NBS) is a rare autosomal recessive disorder caused by hypomorphic mutations of NBS1. NBS1 is a member of the MRE11A-RAD50-NBS1 (MRN) complex which binds DNA double-strand breaks and activates the DNA Damage Response (DDR). Nbs1 inactivation in neural progenitor cells leads to microcephaly and premature death. Interestingly, p53 homozygous deletion rescues the NBS1-deficient phenotype allowing long-term survival. The objective of this work was to determine whether simultaneous inactivation of Nbs1 and p53 in neural progenitors triggered brain tumorigenesis and if so in which category this tumour could be classified.We generated a mouse model with simultaneous genetic inactivation of Nbs1 and p53 in embryonic neural stem cells and analysed the arising tumours with in-depth molecular analyses including immunohistochemistry, array Comparative Genomic Hybridization (aCGH), whole exome-sequencing and RNA-sequencing.NBS1/P53-deficient mice develop high-grade gliomas (HGG) arising in the olfactory bulbs and the cortex along the rostral migratory stream, and to a lower incidence of medulloblastomas. In-depth molecular analyses using immunohistochemistry, array Comparative Genomic Hybridization (aCGH), whole exome-sequencing and RNA-sequencing revealed striking similarities to paediatric human HGG with shared features with Radiation-Induced Gliomas: RIG.Our findings show that concomitant inactivation of Nbs1 and p53 in mice promotes HGG with RIG features. This model could be useful for preclinical studies to improve the prognosis of these deadly tumours, but it also highlights the singularity of NBS1 among the other DNA damage response proteins in the aetiology of brain tumours.