Molecular neuro-oncology in clinical practice: a new horizon

Summary

Primary brain tumours are heterogeneous in histology, genetics, and outcome. Although WHO's classification of tumours of the CNS has greatly helped to standardise diagnostic criteria worldwide, it does not consider the substantial progress that has been made in the molecular classification of many brain tumours. Recent practice-changing clinical trials have defined a role for routine assessment of MGMT promoter methylation in glioblastomas in elderly people, and 1p and 19q codeletions in anaplastic oligodendroglial tumours. Moreover, large-scale molecular profiling approaches have identified new mutations in gliomas, affecting IDH1, IDH2, H3F3, ATRX, and CIC, which has allowed subclassification of gliomas into distinct molecular subgroups with characteristic features of age, localisation, and outcome. However, these molecular approaches cannot yet predict patients' benefit from therapeutic interventions. Similarly, transcriptome-based classification of medulloblastoma has delineated four variants that might now be candidate diseases in which to explore novel targeted agents.

Introduction

The WHO classification of tumours of the CNS distinguishes tumours by histological criteria and, based on morphological features of anaplasia, allocates a malignancy grade ranging from I to IV for each tumour, if applicable. Traditionally, the nomenclature of brain tumours is based on the presumed cell of origin, which is deduced mainly from cytological similarities between the tumour cells and the normal cell types in the CNS and its coverings (appendix).¹

Historically, histopathology was the first method used to distinguish brain tumours of different grades of malignancy and (presumed) different histogenetic origin, with the goal to provide clinicians with prognostic information. Histopathological classification alone has its limitations, but immunohistochemical markers can help to differentiate different tumour entities with higher certainty, thereby reducing interobserver variability, and allowing for better characterisation of novel tumour entities and variants. The use of molecular markers that carry both diagnostic and prognostic information of tumours with histologically similar appearance adds another level of complexity. Nevertheless, molecular markers have become an integral part of tumour assessment in modern neuro-oncology practice because they provide useful information in addition to the WHO classification, and molecular-marker status now guides clinical decision making, at least in subtypes of gliomas.² At the same time, several genome-wide or transcriptome-wide molecular approaches to classify brain tumours indicate that single marker profiling might only be a transient diagnostic standard, which could soon be replaced at reasonable cost by tumour genome-wide molecular profiling techniques, including array-based methods and diagnostic next generation sequencing. In this Review we draw attention to recent advances in the molecular diagnosis and classification of primary brain tumours and discuss how these advances inform therapeutic decisions.