Molecular diversity in isocitrate dehydrogenase-wild-type glioblastoma

Jawad Fares; Yizhou Wan; Richard Mair; Stephen J Price

doi:10.1093/braincomms/fcae108

Molecular diversity in isocitrate dehydrogenase-wild-type glioblastoma

Brain Commun. 2024 Mar 27;6(2):fcae108. doi: 10.1093/braincomms/fcae108. eCollection 2024.

Authors

Jawad Fares^{1

2

3}, Yizhou Wan^{1

2}, Richard Mair¹, Stephen J Price^{1

2}

Affiliations

¹ Academic Neurosurgery Division, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
² Cambridge Brain Tumour Imaging Laboratory, Division of Neurosurgery, Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0QQ, UK.
³ Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.

Abstract

In the dynamic landscape of glioblastoma, the 2021 World Health Organization Classification of Central Nervous System tumours endeavoured to establish biological homogeneity, yet isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma persists as a tapestry of clinical and molecular diversity. Intertumoural heterogeneity in IDH-wt glioblastoma presents a formidable challenge in treatment strategies. Recent strides in genetics and molecular biology have enhanced diagnostic precision, revealing distinct subtypes and invasive patterns that influence survival in patients with IDH-wt glioblastoma. Genetic and molecular biomarkers, such as the overexpression of neurofibromin 1, phosphatase and tensin homolog and/or cyclin-dependent kinase inhibitor 2A, along with specific immune cell abundance and neurotransmitters, correlate with favourable outcomes. Conversely, increased expression of epidermal growth factor receptor tyrosine kinase, platelet-derived growth factor receptor alpha and/or vascular endothelial growth factor receptor, coupled with the prevalence of glioma stem cells, tumour-associated myeloid cells, regulatory T cells and exhausted effector cells, signifies an unfavourable prognosis. The methylation status of O⁶-methylguanine-DNA methyltransferase and the influence of microenvironmental factors and neurotransmitters further shape treatment responses. Understanding intertumoural heterogeneity is complemented by insights into intratumoural dynamics and cellular interactions within the tumour microenvironment. Glioma stem cells and immune cell composition significantly impact progression and outcomes, emphasizing the need for personalized therapies targeting pro-tumoural signalling pathways and resistance mechanisms. A successful glioblastoma management demands biomarker identification, combination therapies and a nuanced approach considering intratumoural variability. These advancements herald a transformative era in glioblastoma comprehension and treatment.

Keywords: IDH-wild-type; glioblastoma; heterogeneity; machine learning; neuroimaging.

Publication types

Review