Methylation Profiling in Diffuse Gliomas: Diagnostic Value and Considerations

SIMPLE SUMMARY: Diffuse gliomas are a type of brain tumour afflicting adults and children, often with a fatal outcome. An accurate diagnosis is required to give patients correct treatment and for the allocation of homogeneous diagnoses into clinical trials. Diagnosis is historically based upon the visual appearance of the tumour in a microscope, but is nowadays also complemented by molecular analyses of how the tumour cells’ DNA has altered. One aspect that has gained considerable interest is the so-called DNA methylation pattern of the tumour. The pattern is a sort of bar code for the tumour, and this bar code differs for various tumour types. As such, the methylation pattern can be used for the diagnosis of tumours and stratification into methylation subclasses. Here, we review the utility of DNA methylation as a diagnostic tool in diffuse gliomas and considerations for its use. ABSTRACT: Diffuse gliomas cause significant morbidity across all age groups, despite decades of intensive research efforts. Here, we review the differences in diffuse gliomas in adults and children, as well as the World Health Organisation (WHO) 2021 classification of these tumours. We explain how DNA methylation-based classification works and list the methylation-based tumour types and subclasses for adult and paediatric diffuse gliomas. The benefits and utility of methylation-based classification in diffuse gliomas demonstrated to date are described. This entails the identification of novel tumour types/subclasses, patient stratification and targeted treatment/clinical management, and alterations in the clinical diagnosis in favour of the methylation-based over the histopathological diagnosis. Finally, we address several considerations regarding the use of DNA methylation profiling as a diagnostic tool, e.g., the threshold of the classifier, the calibrated score, tumour cell content and intratumour heterogeneity.