Abstract 1158: Hypermutation patterns shape tumorigenesis and immunotherapy response in mismatch repair deficient glioma

Abstract Primary mismatch repair deficient (priMMRD) glioma are deadly cancers comprising 5-10% of gliomas in children and young adults. PriMMRD glioma are characterized by universal hypermutation, resistance to chemo-irradation, and striking, but hetergeonous, responses to anti-PD1 immunotherapy. To elucidate the impact of replication-error driven mutagenesis on priMMRD glioma evolution and their heterogenous clinical courses, we analyzed genomic, methylomic, immune, and clinical data on a large cohort of priMMRD glioma (n=162) from the the International Replication Repair Deficiency Consortium. MMRD contributed to high microsatellite instability and hypermutation resulting in global DNA hypomethylation compared to non-MMRD gliomas and potentially affecting their classification. Recurrent somatic driver mutations in replicative polymerases and IDH1 stratified priMMRD gliomas into 3 distinct genetic and clinical subgroups: priMMRD1 (MMRD+POLE/POLD1, 56%), priMMRD2 (MMRD-only, 27%), and priMMRD3 (MMRD+IDH1, 17%). PriMMRD1 gliomas, which harbor complete replication repair deficiency, originated from germline biallelic MMRD (CMMRD), occurred at young ages, and exhibited ultrahypermutation. PriMMRD2 gliomas were enriched for monoallelic germline MMRD (Lynch syndrome) and older ages. Finally, IDH1-driven priMMRD3 gliomas harboured germline mutations in MutSα (MSH2/MSH6), lower mutation burden, and distinct imaging patterns. Subgroups also utilized different mechanisms of genomic instability: while priMMRD1 gliomas harboured frequent point mutations in glioma drivers, priMMRD2 and priMMRD3 gliomas had higher rates of copy alteration in the same genes, including CDKN2A (P<0.0001) and PTEN (P<0.0001). Driver mutations observed in MMRD-driven gliomagenesis could be explained by the specific trinucleotide contexts that compose MMRD mutational signatures. Hotspot mutations in TP53 and IDH1 occurred in contexts commonly mutated by MMRD, while pediatric glioma drivers (BRAF/H3-3A), which do not arise from frequently mutated contexts, were rare. Using mutational signatures and variant allele fractions, we built a model of MMRD gliomagenesis where TP53 mutations occur early, followed by secondary mutations in POLE/POLD1, IDH1, and other glioma drivers. PriMMRD glioma subgroups differed in their immune microenvironment and response to immunotherapy: priMMRD1 gliomas were associated with the highest 2-year overall survival on anti-PD1 monotherapy (75%), exhibited pro-immune expression signatures, and high CD8+ T-cell infiltration, contrasting priMMRD2 (24%) and priMMRD3 gliomas (0%). These findings suggest that MMRD mutagenesis shapes the unique landscape of priMMRD glioma through driver mutation acquisition and responses to immunotherapy, providing a rational approach for the refinement of subgroup-specific immunotherapy combinations. Citation Format: Nicholas R. Fernandez, Yuan Chang, Nuno M. Nunes, Jose R. Dimayacyac, Adrian Levine, Amit Ringel, Logine Negm, Ayse B. Ercan, Julian Hess, Olfat Ahmad, Caitlin Lee, Lucie Stengs, Vanessa Bianchi, Melissa Edwards, Sheradan Doherty, Jiil Chung, Liana Nobre, Julie Bennett, Andrew J. Dodgshun, David TW Jones, Stefan M. Pfister, Anita Villani, David Malkin, Vijay Ramaswamy, Annie Huang, Eric Bouffet, Melyssa Aronson, Peter B. Dirks, Adam Shlien, Gad Getz, Yosef E. Maruvka, Birgit Ertl-Wagner, Cynthia Hawkins, Anirban Das, Uri Tabori. Hypermutation patterns shape tumorigenesis and immunotherapy response in mismatch repair deficient glioma [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 1158.