PNKP and central nervous system cancer: In conclusion, although functional studies in a mouse model are needed to characterize the influence of both the novel P101L and previously described T323M PNKP alterations on brain tumor initiation, we speculate that mutant PNKP-driven impaired DNA damage response and higher spontaneous mutation rates contributed to the generation of pediatric glioma associated driver mutations such as TP53 and ATRX in the clinical case described.