Abstract Replication repair deficiency (RRD), caused by germline biallelic mutations in mismatch repair, leads to hypermutant brain tumour development in children and adolescents. RRD medulloblastoma have been reported but how RRD driven mutagenesis contributes to their clinical, genomic, and immune profiles is unknown. Through the International RRD Consortium, we enrolled 43 RRD medulloblastoma, analysed their exomes, methylomes, transcriptomes, and clinical outcomes. To better understand the mechanisms underlying their development and to assess preclinical responses to immunotherapy, we analyzed the histology and exomes of embryonal brain tumours developed in RRD mouse models (Nestin-Cre+/MSH2LoxP/LoxP/POLES459F/+). RRD medulloblastoma were enriched for anaplasia (61%), localised disease (77%), and harboured hypermutation and microsatellite instability, contrasting with “quiet” genomic profiles of non-RRD medulloblastoma (p0.0001). Point mutations were frequent in POLE/POLD1 (80%), TP53 (48%), SHH pathway genes (56%) and, notably, glioma driver genes (ATRX, NF1, RB1: 50%). TP53 hotspot mutations were distinct from non-RRD medulloblastoma and occurred in trinucleotide sequence contexts which were highly mutated by RRD mutational signatures, suggesting that replication errors shape their genetic evolution. Copy-number changes were infrequent (20%) and inversely correlated with tumour mutation burden. While most did not classify with high confidence (0.9) on DNA methylation subtyping tools, RRD medulloblastoma shared methylation programs with SHH medulloblastoma. Non-promoter genomic regions were hypomethylated relative to non-RRD medulloblastoma, partially explaining their failure to perform in DNA methylation classifiers. Transcriptomics reflected shared expression programs between RRD and SHH medulloblastomas. RRD medulloblastoma demonstrated high CD8+ T-cell infiltration and response to anti-PD1 monotherapy, with 60% three-year progression-free survival. Outcome was worse for tumours with TP53-mutation (p=0.04). Recurrent/progressive RRD medulloblastoma treated with anti-PD1 monotherapy had prolonged survival compared those which were not (p = 0.02), including responses in TP53-mutant tumours. RRD mouse models developed tumours that mirrored histological and genetic profiles of human disease and responded to anti-PD1 monotherapy, highlighting their relevance for future preclinical studies. Human RRD medulloblastoma are distinguished by their unique spectrum of driver mutations and hypomethylation profiles, shaped by RRD mutagenesis. Mouse models recapitulate human features and offer a mechanistic model for tumorigenesis and immunotherapy responses. Importantly, immune-hot microenvironments in RRD medulloblastoma contribute to successful salvage therapy for tumours failing chemo-radiation. Citation Format: Nicholas R. Fernandez, Anirban Das, Adrian Levine, Kyle Smith, Evan Wang, Melissa Galati, Zoya Aamir, Jiil Chung, Logine Negm, Hope Friedman, Katharine O'Flaherty, Owen Crump, Quang M. Trinh, Nuno M. Nunes, Vanessa Bianchi, Lucie Stengs, Melissa Edwards, Lincoln Stein, Eric Bouffet, Michael D. Taylor, Paul Northcott, Vijay Ramaswamy, Cynthia Hawkins, Uri Tabori. Trans-species analysis of replication repair deficient medulloblastoma and response to immune checkpoint inhibition: An IRRDC report abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1159.
Fernández et al. (Fri,) studied this question.