Mechanisms and therapeutic implications of hypermutation in gliomas.

ABSTRACT: A high tumour mutational burden (hypermutation) is observed in some gliomas^1-5; 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 te

SUBMITTER: Touat M 

PROVIDER: S-EPMC8235024 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature