Neurofibromatosis and Peripheral Nerve Sheath Tumor Pathology

Neurofibromatosis encompasses a group of autosomal-dominant syndromes characterised by cutaneous, neurological and skeletal manifestations stemming from mutations in tumour suppressor genes. Type 1 (NF1), by far the most common, arises from germline loss of neurofibromin, a negative regulator of RAS signalling, leading to the development of benign neurofibromas that can undergo malignant transformation into malignant peripheral nerve sheath tumours (MPNSTs). Type 2 (NF2) and schwannomatosis involve defects in merlin and SMARCB1/LZTR1 respectively, and primarily give rise to schwannomas. Peripheral nerve sheath tumour pathology spans a spectrum from colourful cutaneous lesions to aggressive sarcomas; histological hallmarks include proliferation of Schwann-cell-lineage elements, variable collagenous stroma and changes in tumour microenvironment, such as immune cell infiltration and epigenetic remodelling. The unpredictable evolution of benign lesions into life-threatening MPNSTs underscores the need for reliable biomarkers, improved imaging modalities and targeted therapies. Advances in genomic and epigenomic profiling have begun to reveal trajectories of tumour evolution, identify molecular subtypes with distinct oncogenic drivers and inform the rational design of pathway-directed treatments.

Research from Nature Portfolio

Recent studies have applied integrated molecular analyses to define clinically actionable subgroups within MPNST. Multiplatform profiling of methylome and transcriptome data has delineated two discrete subtypes driven by aberrant SHH and WNT/β-catenin/CCND1 pathway activation respectively, each with characteristic transcriptional and cellular phenotypes resembling neural crest-like or Schwann cell precursor-like lineages and differential sensitivity to pathway inhibitors. Foundational genomic surveys have further uncovered recurrent mutations in NF1, SUZ12, EED, TP53 and CDKN2A, and revealed diverse secondary Ras pathway-activating alterations that contribute to tumour heterogeneity and resistance mechanisms. These works establish a refined molecular taxonomy of MPNST, paving the way for stratified clinical trials of targeted inhibitors.

Neurofibromatosis and Peripheral Nerve Sheath Tumor Pathology publication trend

The graph below shows the total number of articles in neurofibromatosis and peripheral nerve sheath tumor pathology across all publications each year (not limited to Nature Index journals).

Technical terms

Neurofibromin (NF1): A tumour suppressor protein that downregulates RAS signalling, loss of which underlies NF1 syndrome.

Malignant peripheral nerve sheath tumour (MPNST): A high-grade sarcoma arising from peripheral nerve sheath elements, often in NF1 patients.

Schwann cell precursor: An embryonic cell type in the Schwann cell lineage implicated in tumourigenesis of distinct MPNST subgroups.

Cell-free DNA (cfDNA): Fragments of tumour-derived DNA circulating in blood, used for non-invasive genomic profiling.

H3K27 trimethylation (H3K27me3): An epigenetic mark deposited by Polycomb repressive complex 2, loss of which is linked to specific MPNST evolution pathways.

References

1. Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA. Cancer Discovery (2023).
2. Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities. Nature Communications (2023).
3. Revised diagnostic criteria for neurofibromatosis type 1 and Legius syndrome: an international consensus recommendation. Genetics in Medicine (2021).
4. Current Understanding of Neurofibromatosis Type 1, 2, and Schwannomatosis. International Journal of Molecular Sciences (2021).
5. The genomic landscape of malignant peripheral nerve sheath tumors: diverse drivers of Ras pathway activation. Scientific Reports (2017).