Abstract Objectives Primary mismatch repair deficient high-grade glioma (priMMRD-HGG) are aggressive tumours distinguished by pediatric age of onset, chemotherapy resistance, and result from germline replication repair deficiency. While a subset responds to immune checkpoint inhibition (ICI), overall survival is mixed despite their elevated tumour mutation burden. Methods We sought to elucidate the impact of elevated mutation accumulation on their biology, clinical presentation, and outcomes through comprehensive analysis on the exomes and clinical profiles of 162 priMMRD-HGG. We analyzed these with respect to their tumour immune microenvironments and responses to anti-PD-1 monotherapy through the International Replication Repair Deficiency Consortium. Results We identified three subgroups of priMMRD-glioma with distinct genetics, biology, and therapy response based on somatic driver mutations in polymerase proofreading (POLE/POLD1) or IDH1: priMMRD1 (MMRD + polymerase proofreading deficiency; 56%), priMMRD2 (MMRD-only; 27%), and priMMRD3 (MMRD + IDH1; 17%). PriMMRD1-glioma were enriched for ultrahypermutation (median: 420-mutations/megabase), early age of onset, constitutional mismatch repair deficiency, and cystic-necrotic appearance. PriMMRD-2 gliomas were enriched for older age at diagnosis and Lynch Syndrome. PriMMRD3-gliomas presented in older children, with forebrain localization, and diffuse infiltration of surrounding brain tissue. PriMMRD-glioma subgroups arose from distinct germline MMRD-genotypes and displayed a preference point mutation or copy number alteration which correlated with replication repair integrity. Recurrent driver mutations hotspots in IDH1 and TP53 were associated with specific mutational signatures, suggesting that MMRD directly shapes the genetic drivers observed in these tumours and offers a rational for neoantigen vaccine strategies. PriMMRD1-gliomas, which were immune-inflamed, had significantly improved 24-month post-ICI survival of 75% compared to 43% in priMMRD2 and 33% in priMMRD3 (p 0.0001). Conclusion Our results detail the impact of replication errors on the evolution of priMMRD-HGG. Furthermore, we offer a rational approach to subgroup specific immunotherapy combinations targeting each genetic subgroup.
Das et al. (Tue,) studied this question.