Molecular diversity in isocitrate dehydrogenase-wild-type glioblastoma

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.

Graphical abstract

Figure 1

Simplified version of the World Health Organization 2021 classification of diffuse glioma. For the diagnosis of IDH-wild-type glioblastoma, tumour cell has to have an IDH wild-type phenotype, and at least one of the following: EGFR gene amplification, telomerase reverse transcriptase promoter mutation, chromosome +7/−10, angiogenesis and/or necrosis.

Figure 2

Expression of IDH in glioblastoma. IDH enzymes maintain cellular homeostasis by converting isocitrate to alpha-ketoglutarate. IDH mutations cause alpha-ketoglutarate to be converted to 2-hydroxyglutarate. Accumulation of 2-hydroxyglutarate causes the methylation of DNA and histones, leading to distinct metabolic and epigenetic characteristics, as well as a differential response to therapeutic interventions. IDH-mutated gliomas possess unique genetic and clinical features, with patients displaying improved prognoses compared to those with wild-type IDH genes. Nicotinamide adenine dinucleotide phosphate (NADPH).

Figure 3

Oncogenes versus tumour suppressor genes in glioblastoma. EGFR is frequently mutated in glioblastoma and constitutively activates several signalling pathways, inhibits apoptotic cell death and increases growth and invasiveness of glioblastoma cells. PDGF and PDGFR are overexpressed in glioblastomas, particularly, PDGFRA. The overexpression of PDGFRA is associated with more aggressive phenotypes and poorer survival outcomes. The NF1 gene encodes neurofibromin, which inhibits the RAS/MAPK signalling pathway. Inactivation of two NF1 alleles is required for glioma formation. Vascular endothelial growth factor receptor (VEGFR), KRAS (Kirsten rat sarcoma), RAS (rat sarcoma), RAF (rapidly accelerated fibrosarcoma), MEK (mitogen-activated protein kinase), ERK (extracellular signal-regulated kinase), PI3K (phosphoinositide 3-kinase), AKT (protein kinase B), PTEN (phosphatase and tensin homolog), BCL-XL (B-cell lymphoma-extra large), RB1 (retinoblastoma 1), MYC (myelocytomatosis oncogene), GAP (GTPase-activating protein), GDP (guanosine diphosphate), GTP (guanosine triphosphate) and GEF (guanine nucleotide exchange factor).

Figure 4

MGMT methylation in glioblastoma. Temozolomide treatment induces DNA damage, which can be neutralized by the expression of MGMT in glioblastoma cells, thereby restoring DNA integrity and allowing glioblastomas to evade chemotherapeutic toxicity. However, deficient mismatch repair, through MGMT methylation (i.e. deactivation), can lead to DNA strand breaks and glioma cell death.

Figure 5

Intertumoural heterogeneity as a function of cellular signatures in glioblastoma. The abundance of stem cells and tumour-associated myeloid cells and macrophages predict more aggressive tumour subtypes and therapeutic resistance. GSCs are characterized by their self-renewal, tumour initiation capacity, continuous proliferation and the expression of a set of stem cell markers. Chemotherapeutic treatment of malignant gliomas can effectively target differentiated and nontumourigenic cancer cells that are highly proliferative; however, GSCs remain unaffected, which later leads to tumour relapse and recurrence.

Figure 6

Intratumoural heterogeneity informs intertumoural heterogeneity. (Upper left) The presence of cytotoxic and effector immune cells leads to better immune responses against glioblastoma. In contrast, the abundance of tumour-associated immune cells leads to immunosuppression and increased gliomagenesis. (Upper right) Release of NLGN3 by neurons and glutamate and dopamine in the neuron-tumour synapses leads to calcium influx into the glioma cell, activating signalling pathways that promote glioma progression and invasiveness. Glioma cells can release TSP-1 that enhances neuronal–tumoural interactions and enforces pro-tumoural signalling. Influx of Cl⁻ through GABAergic channels into the glioma cell inhibits progression. (Bottom) In well perfused tumour parts, oxygenation promotes HIF1A degradation. As the glioma proliferates, it outgrows its vascularization and releases pro-coagulation factors that lead to microvascular thrombosis. This causes hypoxia and the release of HIF1A, which triggers angiogenesis and increases tumoural perfusion. Tumour cells in perinecrotic areas invade areas with better perfusion, increasing invasiveness of glioma and decreasing survival. NKT1 (natural killer T cell type 1), M1 (type 1 macrophage), N1 (neutrophil type 1), DC (dendritic cell), Th1 (type 1 T helper cell), NK1 (natural killer cell type 1), N2 (neutrophil type 2), Treg (regulatory T cell), M2 (type 2 macrophage), MDSC (myeloid-derived suppressor cell), Th2 (type 2 T helper cell), NK2 (natural killer cell type 2), VHL (Von Hippel-Lindau) and VEGF (vascular endothelial growth factor).

Figure 7

Intertumoural heterogeneity in glioblastoma. Preclinical and clinical investigations have shown that intertumoural heterogeneity in glioblastoma affects tumoural behaviour, response to therapy and prognostic outcomes. Overexpression of NF1, PTEN and/or CDKN2A has been associated with better prognosis in glioblastoma. Conversely, overexpression of EGFR, PDGFRA and/or Vascular endothelial growth factor receptor increases glioblastoma proliferation and leads to worse prognosis. MGMT methylation dictates response to temozolomide. While de novo hypermutation is associated with better responses to immunotherapy, therapy-induced hypermutation has been associated with worse outcomes. In the tumour microenvironment, the abundance of natural killer/T cell type 1 effector cells, type 1 macrophage-phenotype myeloid cells, neutrophil type 1-phenotype neutrophils and dendritic cells is associated with better response against glioblastoma. Conversely, the predominance of glioma stem cells, TAMs, regulatory T cells and exhausted effector cells is associated with glioblastoma proliferation and resistance to therapy. Microenvironmental factors such as GABA and serotonin have been associated with inhibitory effects on tumour growth. On the other hand, glutamate, dopamine, along with NLGN3, TSP-1 and HIF factors promote tumoural proliferation and progression.