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Background: Gliomas are a major cause of cancer-related death among children, adolescents, and young adults (age 0-40 years). Primary mismatch repair deficiency (MMRD) is a pan-cancer mechanism with unique biology and therapeutic opportunities. We aimed to determine the extent and impact of primary MMRD in gliomas among children, adolescents, and young adults., Methods: Clinical and molecular data were collected from a population-based cohort of children, adolescents, and young adults with gliomas from Toronto (TOR-Ped, age 0-18 years, collected Jan 1, 2000, to Dec 31, 2021; and TOR-AYA, age 18-40 years, collected Jan 1, 2000, to June 30, 2019). Additional validation paediatric cohorts from St Jude Children's Research Hospital (0-18 years, 2015-21) and the Children's Brain Tumor Network (0-18 years, 1981-2021) were used. Functional genomic tools were applied with the primary aim of assessing primary MMRD prevalence among glioma subgroups and germline impact. To evaluate the effect of primary MMRD on therapy and overall survival, Kaplan-Meier estimates were used on an additional cohort of patients with primary MMRD gliomas treated with immunotherapy., Findings: 1389 gliomas were included in the study. The prevalence of primary MMRD ranged between 3·7% and 12·4% in high-grade gliomas (overall 30 of 483; 6·2%, 95% CI 4·2-8·7) and less than 1% in low-grade gliomas (four of 899; 0·4%, 0·1-1·1; p<0·0001 by χ 2 test). Specific molecular analysis for all gliomas showed that primary MMRD was absent among oligodendrogliomas (none of 67) and uncommon in BRAF V600E gliomas (one of 110) and histone mutant-driven gliomas (one of 150). In the paediatric age group (<18 years), primary MMRD was common in IDH WT and H3 WT gliomas harbouring pathogenic TP53 variants (21 of 61; 34·4%, 22·7-47·7) and in malignant IDH mut gliomas (five of eight; 62·5%, 24·5-91·5). Germline aetiology accounted for 33 (94·3%) of 35 primary MMRD gliomas, including children, adolescents, and young adults with previously unrecognised Lynch syndrome. Survival was poor for patients with primary MMRD gliomas. Particularly poor survival was observed for those with IDH mut astrocytomas with primary MMRD when compared with those with mismatch repair-proficient gliomas (HR 12·6, 95% CI 2·8-57·5; p=0·0011 by multivariable Cox regression). Immune checkpoint blockade was associated with improved survival for patients with primary MMRD gliomas compared with conventional chemoradiotherapy regimens (HR 0·4, 0·3-0·7; p=0·0017 by multivariable Cox regression), regardless of age or germline status., Interpretation: Primary MMRD is more common than previously reported in gliomas in children, adolescents, and young adults, is enriched in specific molecular subgroups, and is associated with poor outcomes. Accurate detection, genetic testing, early diagnosis through surveillance, and implementation of immunotherapy might improve survival for these patients., Funding: The Canadian Institutes for Health Research, Stand Up to Cancer-Bristol Myers Squibb Catalyst, US National Institutes of Health, Canadian Cancer Society, Brain Canada, The V Foundation for Cancer Research, BioCanRx, Canada's Immunotherapy Network, Harry and Agnieszka Hall, Meagan's Hug, BRAINchild Canada, and the LivWise Foundation., Competing Interests: Declaration of interests AFG reports consulting fees and speaker honoraria from Servier Canada. DST reports consulting fees for Need (getneed.com). GG receives research funds from IBM, Pharmacyclics/AbbVie, Bayer, Genentech, Calico, and Ultima Genomics. GG is an inventor on patent applications related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSIDetect/MSEye, LOGIC, and MinimuMM-seq; is a founder, consultant, and has privately held equity in Scorpion Therapeutics; is a founder of and has privately held equity in PreDICTA Biosciences; and has consulted for Merck. JK reports funding from Canadian Institutes of Health Research and Brain Canada; consulting as a neuropathologist for the Ontario Forensic Pathology Services; provides expert witness testimony, support to attend Canadian and American Association of Neuropathologists annual meetings, and support from the Department of Laboratory Medicine and Molecular Biology at Sunnybrook Health Science Centre to undertake a forensic neuropathology sabbatical; is the Vice Chair of the Royal College of Physicians and Surgeons of Canada Specialty Committee in Neuropathology; and reports leadership positions in the Canadian Association of Neuropathologists. SDa reports grants from Ontario Institute for Cancer Research, New Frontiers in Research Fund, Canadian Institutes of Health Research, Canadian Cancer Society, Breast Cancer Canada, American Brain Tumor Association, Synaptive Medical, VPIX Medical, Gratitude 10, and Macbeth Family Trust; is the Keenan Chair in Surgery at the Temerty Faculty of Medicine at the University of Toronto; reports royalties or licenses from Oxford University Press; and holds leaderships roles at Ontario Health (Cancer Care Ontario) and Subortical Surgery Group. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Constitutional mismatch repair deficiency (CMMRD) is a rare syndrome characterized by an increased incidence of cancer. It is caused by biallelic germline mutations in one of the four mismatch repair genes (MMR) genes: MLH1, MSH2, MSH6, or PMS2. Accurate diagnosis accompanied by a proper molecular genetic examination plays a crucial role in cancer management and also has implications for other family members. In this report, we share the impact of the diagnosis and challenges during the clinical management of two brothers with CMMRD from a non-consanguineous family harbouring compound heterozygous variants in the PMS2 gene. Both brothers presented with different phenotypic manifestations and cancer spectrum. Treatment involving immune checkpoint inhibitors significantly contributed to prolonged survival in both patients affected by lethal gliomas. The uniform hypermutation also allowed immune-directed treatment using nivolumab for the B-cell lymphoma, thereby limiting the intensive chemotherapy exposure in this young patient who remains at risk for subsequent malignancies., (© 2024. The Author(s).)

Immune checkpoint inhibition (ICI) is effective for replication-repair-deficient, high-grade gliomas (RRD-HGG). The clinical/biological impact of immune-directed approaches after failing ICI monotherapy is unknown. We performed an international study on 75 patients treated with anti-PD-1; 20 are progression free (median follow-up, 3.7 years). After second progression/recurrence (n = 55), continuing ICI-based salvage prolonged survival to 11.6 months (n = 38; P < 0.001), particularly for those with extreme mutation burden (P = 0.03). Delayed, sustained responses were observed, associated with changes in mutational spectra and the immune microenvironment. Response to reirradiation was explained by an absence of deleterious postradiation indel signatures (ID8). CTLA4 expression increased over time, and subsequent CTLA4 inhibition resulted in response/stable disease in 75%. RAS-MAPK-pathway inhibition led to the reinvigoration of peripheral immune and radiologic responses. Local (flare) and systemic immune adverse events were frequent (biallelic mismatch-repair deficiency > Lynch syndrome). We provide a mechanistic rationale for the sustained benefit in RRD-HGG from immune-directed/synergistic salvage therapies. Future approaches need to be tailored to patient and tumor biology., Significance: Hypermutant RRD-HGG are susceptible to checkpoint inhibitors beyond initial progression, leading to improved survival when reirradiation and synergistic immune/targeted agents are added. This is driven by their unique biological and immune properties, which evolve over time. Future research should focus on combinatorial regimens that increase patient survival while limiting immune toxicity. This article is featured in Selected Articles from This Issue, p. 201., (©2023 American Association for Cancer Research.)

Phylogenetic comparative methods are increasingly used to test hypotheses about the evolutionary processes that drive divergence in gene expression among species. However, it is unknown whether the distributional assumptions of phylogenetic models designed for quantitative phenotypic traits are realistic for expression data and importantly, the reliability of conclusions of phylogenetic comparative studies of gene expression may depend on whether the data is well described by the chosen model. To evaluate this, we first fit several phylogenetic models of trait evolution to 8 previously published comparative expression datasets, comprising a total of 54,774 genes with 145,927 unique gene-tissue combinations. Using a previously developed approach, we then assessed how well the best model of the set described the data in an absolute (not just relative) sense. First, we find that Ornstein-Uhlenbeck models, in which expression values are constrained around an optimum, were the preferred models for 66% of gene-tissue combinations. Second, we find that for 61% of gene-tissue combinations, the best-fit model of the set was found to perform well; the rest were found to be performing poorly by at least one of the test statistics we examined. Third, we find that when simple models do not perform well, this appears to be typically a consequence of failing to fully account for heterogeneity in the rate of the evolution. We advocate that assessment of model performance should become a routine component of phylogenetic comparative expression studies; doing so can improve the reliability of inferences and inspire the development of novel models., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society for Molecular Biology and Evolution.)

Phylogenetic comparative methods are increasingly used to test hypotheses about the evolutionary processes that drive divergence in gene expression among species. However, it is unknown whether the distributional assumptions of phylogenetic models designed for quantitative phenotypic traits are realistic for expression data and importantly, the reliability of conclusions of phylogenetic comparative studies of gene expression may depend on whether the data is well-described by the chosen model. To evaluate this, we first fit several phylogenetic models of trait evolution to 8 previously published comparative expression datasets, comprising a total of 54,774 genes with 145,927 unique gene-tissue combinations. Using a previously developed approach, we then assessed how well the best model of the set described the data in an absolute (not just relative) sense. First, we find that Ornstein-Uhlenbeck models, in which expression values are constrained around an optimum, were the preferred model for 66% of gene-tissue combinations. Second, we find that for 61% of gene-tissue combinations, the best fit model of the set was found to perform well; the rest were found to be performing poorly by at least one of the test statistics we examined. Third, we find that when simple models do not perform well, this appears to be typically a consequence of failing to fully account for heterogeneity in the rate of the evolution. We advocate that assessment of model performance should become a routine component of phylogenetic comparative expression studies; doing so can improve the reliability of inferences and inspire the development of novel models.