复制修复缺陷型髓母细胞瘤及其对免疫检查点抑制反应的跨物种分析：一份IRRDC报告

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 + / MSH2 LoxP/LoxP / POLE S459F/+ ). 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 (p<0.0001). 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.