This research article examines how primary mismatch-repair-deficient high-grade gliomas are categorized into three distinct molecular subgroups based on specific secondary mutations. The study identifies that genomic instability mechanisms dictate whether a tumor develops through point mutations or copy number alterations, creating an inverse relationship between these two genetic events. Notably, the authors found that mutational signatures act as a semi-deterministic force, favoring the emergence of specific driver mutations in genes like TP53 and IDH1 while excluding others. These biological pathways significantly influence the tumor immune microenvironment, leading to varied patient outcomes. For instance, tumors with polymerase proofreading deficiency often show ultrahypermutation and respond well to immunotherapy, whereas IDH1-mutant varieties tend to be resistant. Ultimately, this framework provides a new model for risk stratification and the development of targeted therapeutic strategies for these aggressive brain cancers.

References:

• Fernandez N R, Chang Y, Nunes N M, et al. Patterns of hypermutation shape tumorigenesis and immunotherapy response in mismatch-repair-deficient glioma[J]. Nature genetics, 2025: 1-11.