Abstract
DNA replication-repair deficiency (RRD) arises from pathogenic variants in the mismatch repair and/or polymerase-proofreading genes. Multiple germline cancer predisposition syndromes in children and young adults, including constitutional mismatch repair deficiency (CMMRD), Lynch, polymerase-proofreading deficiency, and rare digenic syndromes can lead to RRD cancers. The most frequent brain tumors in these children are high-grade gliomas. Embryonal tumors like medulloblastoma have also been described. Lower-grade tumors are reported from cancer surveillance initiatives. The latter has an extremely high rate of malignant transformation. Novel functional assays quantifying the genomic microsatellite indel load have been demonstrated to be highly sensitive and specific for the diagnosis of RRD cancers and children with germline CMMRD. Importantly, RRD brain tumors uniformly harbor high mutation and microsatellite burden. High T-cell infiltration makes these aggressive cancers amenable to immune checkpoint inhibition, irrespective of their germline genetic background. Synergistic combinations are reported to be successful in patients failing checkpoint inhibitor monotherapy. Future directions include the development of innovative approaches to improve immune surveillance for RRD brain cancers. Additionally, the use of novel tools including circulating tumor DNA and quantifying microsatellite indel load over time can be useful to monitor disease burden and treatment responses in patients.