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Received: 22 July 2019
Accepted: 4 March 2020
Published online: 15 April 2020
A high tumour mutational burden (hypermutation) is observed in some gliomas1-5; however, the mechanisms by which hypermutation develops and whether it predicts the response to immunotherapy are poorly understood. Here we comprehensively analyse the molecular determinants of mutational burden and signatures in 10,294 gliomas. We delineate two main pathways to hypermutation: a de novo pathway associated with constitutional defects in DNA polymerase and mismatch repair (MMR) genes, and a more common post-treatment pathway, associated with acquired resistance driven by MMR defects in chemotherapy-sensitive gliomas that recur after treatment with the chemotherapy drug temozolomide. Experimentally, the mutational signature of post-treatment hypermutated gliomas was recapitulated by temozolomide-induced damage in cells with MMR deficiency. MMR-deficient gliomas were characterized by a lack of prominent T cell infiltrates, extensive intratumoral heterogeneity, poor patient survival and a low rate of response to PD-1 blockade. Moreover, although bulk analyses did not detect microsatellite instability in MMR-deficient gliomas, single-cell whole-genome sequencing analysis of post-treatment hypermutated glioma cells identified microsatellite mutations.
These results show that chemotherapy can drive the acquisition of hypermutated populations without promoting a response to PD-1 blockade and supports the diagnostic use of mutational burden and signatures in cancer.
Identifying genomic markers of response to immune checkpoint blockade (for example, PD-1 blockade) may benefit cancer patients by providing predictive biomarkers for patient stratification and identifying resistance mechanisms for therapeutic targeting. Glio-mas typically have a low tumour mutational burden (TMB) and a highly immunosuppressive microenvironment-two features associated with immunotherapy resistance. Nevertheless, recent work has suggested that a subset of patients with high-TMB (hypermutated) gliomas might benefit from PD-1 blockade6. Although consistent with data from other cancers7-9, these initial observations were derived from unique disease contexts such as constitutional DNA mismatch-repair (MMR) deficiency syndrome6. Therefore, the extent to which glioma patients at large will benefit from this approach is unknown. While large amounts of genomic data on gliomas exist2,4,5,10,11,12, our understanding of the clinical landscape of hypermutation and the mechanisms that underlie its development remain unclear. Hypermutation is rare in newly-diagnosed gliomas (de novo hypermutation), but common in tumours that have recurred after the use of alkylating agents (post-treatment hypermutation)4'5'10'11. Given that gliomas exhibit substantial inter-patient and intra-tumoral genomic...