Abstract Background Replication repair maintains genomic fidelity. Germline-inherited replication repair deficiency (RRD) leads to hypermutant, early-onset brain tumours. RRD medulloblastoma (MB) are reported but not well-characterized. Methods We performed multi-omic analyses to elucidate the impact of hypermutation on RRD-MB biology and treatment-outcomes. Results RRD-MB (n = 48) were enriched for anaplastic disease (61%). t-SNE analysis suggested SHH-subgroup affinity despite low confidence of classification on the Heidelberg Classifier (78%). Genomic profile displayed microsatellite instability and hypermutation, with frequent somatic mutations in polymerase proofreading genes (80%). Mutations were also common inTP53 (48%), SHH-pathway genes (56%) and, strikingly, glioma driver genes (ATRX,NF1,RB1; 50%). Copy number changes were infrequent. Comparative analysis of variant allele frequency in tumours with both SHH and glioma drivers indicated that SHH-drivers occur first, suggesting that primary tumor identity is defined by an initial combination of cell of origin and genetic alterations. Deconvolution of single-nuclei RNA-sequencing revealed enrichment for astro-glial expression programs exclusive to RRD-MB compared to non-RRD SHH-MB, suggesting a functional impact of glioma driver mutations. Representative RRD-MB mouse models (Nestin-Cre+/MSH2LoxP/LoxP/POLES459F/+) further substantiated human findings, harbouring both SHH- and glioma-drivers, with ultra-hypermutation and mixed embryonal-glial phenotypes. High levels of immune infiltrates (CD8+ T-cell), in both mouse and human tumors, provided biological insights into the immune mechanisms underlying the efficacy of anti-PD1 monotherapy in human RRD-MB, leading to radiological remission in refractory disease and prolonged survival (p = 0.02). Conclusions RRD-MB form a distinct subtype of SHH-activated MB. Their genetic phenotypes are modified by genomic instability leading to point mutations and indels in both SHH and glioma-pathways. Hypermutation and corresponding immune infiltration confer immune checkpoint inhibitor efficacy at recurrence, allowing the development of prospective combined chemo-immunotherapy treatment protocols for patients with high-risk disease.
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