Molecular Pathology of Pediatric Central Nervous System Tumors

Pediatric central nervous system tumours comprise a diverse set of malignancies driven by distinct molecular alterations that underlie diagnosis, prognosis and therapeutic response. Advances in high-throughput sequencing, genome-wide DNA methylation profiling and integrative proteomic analyses have revealed that many tumours previously classified by histology are in fact molecularly heterogeneous. Key entities include medulloblastoma subgroups defined by WNT and SHH pathway alterations, H3-mutant diffuse midline gliomas with Lys27Met substitutions, atypical teratoid/rhabdoid tumours characterised by SMARCB1 loss, embryonal tumours with multilayered rosettes (ETMR) hallmarked by C19MC amplification or DICER1 mutation, and newly recognised CNS neuroblastoma with FOXR2 activation. Epigenetic modifiers, non-coding RNA clusters and histone-modifying enzymes feature prominently in tumourigenesis, often cooperating with mutations in TP53, ATRX or ACVR1 to dictate cellular identity and behaviour. Profiling at the transcriptomic and proteomic level has not only refined classification but also uncovered dependencies on pathways such as proteasome function and MEK/ERK signalling. This molecular insight is driving risk stratification, enabling tailored targeted therapies and informing the design of collaborative registries and trials that span genomics, immunophenotyping and functional modelling.

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Molecular Pathology of Pediatric Central Nervous System Tumors publication trend

The graph below shows the total number of articles in molecular pathology of pediatric central nervous system tumors across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation profiling: Genome-wide analysis of 5-methylcytosine patterns used to classify tumour subtypes.

Transcriptomics: Study of the complete set of RNA transcripts to reveal gene expression programmes.

Proteomics: Comprehensive characterisation of protein abundance and post-translational modifications.

C19MC amplification: Copy-number gain of a chromosome 19 microRNA cluster driving ETMR biology.

FOXR2 activation: Upregulation of the FOXR2 transcription factor, often via genomic rearrangement, defining a CNS neuroblastoma subgroup.

MEK/ERK signalling: A kinase cascade transmitting growth signals; frequently co-opted by oncogenic drivers.

Proteasome inhibitor: Agent that blocks proteasome-mediated protein degradation, inducing tumour cell stress.

References

1. Integrated proteomics spotlight the proteasome as a therapeutic vulnerability in embryonal tumors with multilayered rosettes. Neuro-Oncology (2023).
2. OpenPBTA: The Open Pediatric Brain Tumor Atlas. Cell Genomics (2023).
3. A human embryonic stem cell–based model reveals the cell of origin of FOXR2-activated CNS neuroblastoma. Neuro-Oncology Advances (2024).