Molecular Genetics of Pediatric Gliomas

Pediatric gliomas encompass a diverse spectrum of brain tumours from low-grade pilocytic astrocytomas to diffuse midline and high-grade gliomas. They are distinguished from adult counterparts by recurrent alterations in the mitogen-activated protein kinase (MAPK) pathway, most commonly driven by BRAF fusions, BRAF point mutations and FGFR1 duplications. Histone H3 variants harbouring K27M substitutions define an aggressive subgroup of diffuse midline gliomas with characteristic epigenetic dysregulation. Germline predispositions, such as neurofibromatosis type 1, further contribute via NF1 inactivation and downstream signalling changes. Integrative genomic and epigenomic profiling has delineated molecular subgroups linked to age, tumour location and clinical outcome, while single-cell analyses have revealed interactions between neoplastic glial cells, infiltrating microglia and T cells. These advances underpin the design of targeted inhibitors and immunomodulatory strategies, paving the way for precision medicine in paediatric neuro-oncology.

Research from Nature Portfolio

Recent studies have advanced predictive biomarkers and defined critical neuroimmune interactions. A 2023 investigation developed MAPK inhibitor sensitivity scores based on gene-set enrichment of MAPK-related transcripts. These scores accurately distinguished sensitive and resistant paediatric low-grade glioma models, correlated with trametinib response in patient-derived xenografts and revealed that higher scores coincide with microglial enrichment. Earlier work elucidated a neuron–immune–glioma axis in NF1-associated low-grade gliomas: neuronal midkine activates CD8+ T cells to secrete CCL4, which in turn induces microglial CCL5 production essential for tumour stem cell survival. By mapping these intercellular dependencies, this research highlights potential targets to disrupt the tumour-supportive microenvironment.

Molecular Genetics of Pediatric Gliomas publication trend

The graph below shows the total number of articles in molecular genetics of pediatric gliomas across all publications each year (not limited to Nature Index journals).

Technical terms

MAPK pathway: A signal transduction cascade involving RAS, RAF, MEK and ERK kinases that regulates cell proliferation, differentiation and survival.

BRAF fusion: A gene rearrangement that links BRAF with a partner gene, leading to constitutive activation of the MAPK pathway.

Histone H3K27M mutation: A lysine-to-methionine substitution in histone H3 variants that alters chromatin structure and drives diffuse midline glioma.

ATG16L1::NTRK2 fusion: A novel in-frame fusion combining the autophagy-related ATG16L1 gene with the neurotrophic receptor tyrosine kinase NTRK2, resulting in oncogenic kinase signalling.

Single-cell RNA sequencing: A technique to profile gene expression at the level of individual cells, revealing cellular heterogeneity within tumours.

CCL5: A chemokine secreted by microglia that promotes tumour stem cell survival and supports glioma growth within the microenvironment.

References

1. MAPK inhibitor sensitivity scores predict sensitivity driven by the immune infiltration in pediatric low-grade gliomas. Nature Communications (2023).
2. Midkine activation of CD8+ T cells establishes a neuron–immune–cancer axis responsible for low-grade glioma growth. Nature Communications (2020).
3. Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma. Acta Neuropathologica (2023).
4. A pilocytic astrocytoma with novel ATG16L1::NTRK2 fusion responsive to larotrectinib: a case report with genomic and functional analysis. The Oncologist (2024).
5. Brain injury drives optic glioma formation through neuron-glia signaling. Acta Neuropathologica Communications (2024).