Guest editorial

Abstract

The morphological intricacies of brain tumours and how they influence diagnostic judgements undoubtedly appeal to clinical neuropathologists! However, we are increasingly required to undertake the classification of brain tumours against the backdrop of burgeoning data on their molecular biology and whether this information has diagnostic or therapeutic utility. Methodological advancements have been critical here; a huge amount of data has been generated from array-based technologies, and next-generation sequencing promises even more. Defining both the biological and clinical significance of this information has often been a challenge, requiring optimal evaluation of potential ‘biomarkers’ in the setting of a clinical trial, which allows comparison with clinicopathological variables of known prognostic or predictive utility. However, as these data have been distilled into molecular assays of proven value, the age of diagnostic molecular pathology has undeniably arrived for patients with brain tumours. In this special edition of Neuropathology and Applied Neurobiology, the focus is on how key molecular abnormalities in the commonest adult and paediatric brain tumours are being exploited for preclinical or clinical purposes. There are two main themes: the classification of tumours into molecular subgroups of potential clinicopathological significance, and how genetically engineered mouse models can (i) improve our understanding of the contribution of single or multiple genetic abnormalities to a tumour's phenotype and (ii) be used for preclinical testing of therapeutic agents. In the first review, Richard Gilbertson and his team of researchers review the genesis of brain tumours in the contexts of central nervous system development and neural stem cell biology and discuss how advances in our knowledge of these processes and their dysregulation offer hope for new therapeutic approaches. Their focus is on two paediatric brain tumours, ependymoma and medulloblastoma, for which they have successfully engineered novel molecular subgroup-specific mouse models. The review by Markant and Wechsler-Reya covers advances in our understanding of the medulloblastoma. Medulloblastomas are heterogeneous, separating into four molecular subgroups, which were originally defined using gene expression data. Tumours in each of the subgroups have different clinicopathological and genetic characteristics and are probably derived from distinct cells in the cerebellum or dorsal brain stem. Mouse models of the disease have helped to relate aspects of medulloblastoma biology, particularly dysregulation of cell signalling pathways, to aberrant development of cerebellar granule cell precursors and of neurones in the dorsal brain stem. The molecular biology of paediatric low-grade gliomas is covered in the review by Thangarajh and Gutmann. NF1-associated pilocytic astrocytomas are distinguished from sporadic pilocytic astrocytomas and their differences discussed in terms of genetic abnormalities and potential cells of origin. Mouse models of the disease are reviewed, and the importance of interactions between neoplastic and non-neoplastic cells on tumour growth emphasized. High-grade gliomas, particularly glioblastoma, are covered by authors led by Suzy Baker and Paul Mischel. The review by Rankin, Zhu and Baker focuses on mouse models of high-grade gliomas, describing their generation and diversity and how they can be used for assessing: (i) the incremental integration of specific cell pathway abnormalities in different cell types at different times during central nervous system development; (ii) the acquisition of further genomic abnormalities during disease progression; (iii) glioma biology with respect to interactions between tumour and stroma; and (iv) preclinical testing. Masui, Cloughesy and Mischel describe how, for adult glioblastoma, established genetic abnormalities have already been translated into assays with diagnostic or therapeutic utility and how emerging biological concepts about the molecular subclassification of the disease might yield more. There is an emphasis on the complexities of the glioma cell's molecular circuitry and how targeted therapies need to take account of this if they are to be effective. Neuropathologists should take a leading role in the evolution of brain tumour diagnostics, assuming responsibility for the presentation of histopathological and molecular data, alongside clinical recommendations, in a comprehensive diagnostic report. To do this, they will require knowledge of how advances in our understanding of brain tumour biology can be translated into robust and pertinent assays. These reviews provide some of that knowledge, and I hope that you enjoy reading them as much as I have.