Abstract
Malignant peripheral nerve sheath tumors (MPNSTs) are heterogeneous, highly aggressive tumors with no widely effective treatment other than surgery. Genomic architecture of MPNST is similar to other soft tissue sarcomas, with a relatively modest burden of single nucleotide variants and an elevated frequency of copy-number alterations. Recent advances in genomic studies identified previously unrecognized critical involvement of polycomb repressor complex 2 (PRC2) core components SUZ12 and EED in transition to malignancy. Notably, somatic changes in NF1, CDKN2A/B, and PRC2 are found in most MPNST regardless of their etiology (e.g. neurofibromatosis type 1-associated vs. sporadic vs. radiation-induced), indicating that similar molecular mechanisms impact pathogenesis in these neoplasms. The timing and specific order of genetic or epigenetic changes may, however, explain the typically poorer prognosis of NF1-associated MPNSTs. Studies that reveal genes and regulatory pathways uniquely altered in malignancies are essential to development of targeted tumor therapies. Characterization of MPNST molecular profiles may also contribute to tools for earlier detection, and prediction of prognosis or drug response. Here we review the genetic discoveries and their implications in understanding MPNST biology.
Highlights
Key Points Somatic changes in neurofibromatosis type 1 (NF1), CDKN2A/B, and polycomb repressor complex 2 (PRC2) are found in most Malignant peripheral nerve sheath tumors (MPNSTs) regardless of their etiology, but MPNST are genomically complex, and the order and timing of other genetic events is still poorly understood since most of the available data is based on bulk analysis of tumor specimens. Like most other soft-tissue sarcomas, MPNSTs carry a relatively low burden of single nucleotide variants, but consistently display a high number of structural copy number variants that are relatively unique to each tumor. Studies of epigenetic alterations, such as loss of H3K27 trimethylation and consequent changes in gene expression, may facilitate a better understanding of MPNST biology. Ongoing research to identify correlations between MPNST molecular profiles and clinical behavior may provide more reliable diagnostic and prognostic information
Conditional ablation of Nf1 and Cdkn2a in Schwann cell lineage results in tumors that phenocopy human atypical neurofibromatous neoplasms of uncertain biologic potential” (ANNUBP) and frequently progress to MPNST.[77]. Another genomic study found that most ANFs have normal diploid genomes, low-somatic mutation load, and frequent NF1 inactivation and somatic copy number alteration (SCNA) in CDKN2A/B and SMARCA2.8 Importantly, no mutations, SCNAs or changes in expression were detected in SUZ12, EED, or other PRC2 genes, in contrast with that published in most MPNSTs
Improvement in clinical care is the ultimate goal of understanding genetic drivers of MPNST initiation and progression
Summary
Somatic loss of theY chromosome in leukocytes is an age-related phenomenon in male humans, with greater levels of Y loss associated with increased risk of all cancers.[24] One study reported that the only chromosomal abnormality in an MPNST was deletion of the Y (45,X,-Y).[25] Patient-derived models suggest that sex chromosome aneuploidy may correlate with tumor behavior.
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