Mechanisms and therapeutic implications of hypermutation in gliomas

Nature. 2020 Apr;580(7804):517-523. doi: 10.1038/s41586-020-2209-9. Epub 2020 Apr 15.

Abstract

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.

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / pharmacology
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Brain Neoplasms / genetics*
  • Brain Neoplasms / immunology
  • Brain Neoplasms / therapy*
  • DNA Mismatch Repair / genetics
  • Gene Frequency
  • Genome, Human / drug effects
  • Genome, Human / genetics
  • Glioma / genetics*
  • Glioma / immunology
  • Glioma / therapy*
  • Humans
  • Male
  • Mice
  • Microsatellite Repeats / drug effects
  • Microsatellite Repeats / genetics
  • Mutagenesis / drug effects
  • Mutation* / drug effects
  • Phenotype
  • Prognosis
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Sequence Analysis, DNA
  • Temozolomide / pharmacology
  • Temozolomide / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents, Alkylating
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Temozolomide