Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma

Abstract

Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.

Keywords: epigenetics; gliomas; methylation; paediatric astrocytoma.

FIGURE 1

Incidence rates of brain and other central nervous system (CNS) tumours in children aged 0−14 years (2016–2020, average annual cases = 3427). All tumours and subtypes/grades (meninges, ependymal and gliomas) are based on the 2016 World Health Organization (WHO) classification of tumours of the CNS described in the 25th and 26th Central Brain Tumor Registry of the United States (CBTRUS) statistical report., , NOS, not otherwise specified.

FIGURE 2

Location and primary genetic alterations of prognostic relevance in different molecular subclasses of paediatric astrocytoma (image created with Biorender.com). AA, anaplastic astrocytoma; DA, diffuse astrocytoma; GBM, glioblastoma multiforme; PA, pilocytic astrocytoma.

FIGURE 3

Schematic of the wingless‐related integration sites (WNT) and sonic hedgehog (SHH)‐based molecular signalling pathways across paediatric astrocytoma. Unphosphorylated β‐catenin localises in the nucleus and activates transcription of genes such as C‐MYC, SOX10 and cyclins. In the absence of SHH ligand, smoothened receptor (SMO) is inhibited by protein patched homologue (PTCH), leading to the formation of glioma‐associated oncogene homologue 1 (GLI) repressor that inhibits target genes. SHH ligand interacts with PTCH resulting in a signalling cascade which activates transcription of genes associated with tumour proliferation (image created with Biorender.com). APC, adenomatous polyposis coli; CKIα, casein kinase 1‐alpha; GSK‐3β, glycogen synthase kinase 3 beta; TCF/LEF, T‐cell factor/lymphoid enhancer factor.

FIGURE 4

Schematic of the RAS/MAPK and JAK/STAT‐based molecular signalling pathways altered in paediatric astrocytoma (image created with Biorender.com). GDP, guanosine‐5′‐diphosphate; GTP, guanosine‐5′‐triphosphate; JAK, janus kinase; MAPK, mitogen‐activated protein kinases; STAT, signal transducers and activators of transcription.

FIGURE 5

Important signalling pathways and their potential inhibitors involved in the epigenetic regulation of paediatric high‐ and low‐grade tumours (image created with Biorender.com). BET, bromodomain and extra‐terminal domain; DNMT, DNA methyl transferase; HDAC, histone deacetylase; IDH, mitochondrial isocitrate dehydrogenase; RTK/NTRK, receptor tyrosine kinase/neurotrophic tyrosine kinase receptor.

FIGURE 6

Importance of evaluating both genetic and epigenetic alterations when treating paediatric astrocytomas. Increased tumour metastasis and poor survival is linked to key genetic alterations including v‐raf murine sarcoma viral oncogene homologue B1 (BRAF), mitogen‐activated protein kinases (MAPK) and wingless‐related integration sites (WNT) pathways. Epigenetic deregulation in promoter regions of genes as well as mutations in histone deacetylases is also associated with tumour progression and metastasis. Hence, to ensure maximum therapeutic benefit for paediatric astrocytomas (pA) patients, multi‐omics analysis of the genome, transcriptome and epigenome must be considered when determining the best treatment regimen which will potentially improve survival outcomes for these patients.