Abstract
INTRODUCTION
Neurofibromas, a peripheral nerve sheath tumor commonly associated with Neurofibromatosis Type 1, are broadly categorized as cutaneous or peripheral nerve neurofibromas (localized or plexiform lesions). More recently, atypical neurofibromatous neoplasm of unknown biological potential (ANNUBP) has been described and believed to be a premalignant tumor, although the oncogenic drivers of malignant transformation are poorly understood. In this study, we establish the spectrum of genomic drivers of neuronal tumors, benign and malignant, in sporadic and syndromic settings.
METHODS
We performed multiplatform genomic analysis of a total of 110 cutaneous neurofibromas, peripheral nerve neurofibromas and malignant peripheral nerve sheath tumors (MPNSTs). We performed methylation profiling and RNA sequencing on these tumors. Genomic data was bioinformatically analyzed to identify biologically relevant subgroups. Correlation and validation of key drivers were carried out using a series of IHC and in-vitro studies.
RESULTS
Consensus clustering of methylation data reliably distinguished between cutaneous and peripheral nerve tumors that supports the theory that cutaneous neurofibromas have a distinct cell of origin. Copy number analysis (CNA) identified a loss of 9p in 35% of peripheral nerve neurofibromas. Consensus clustering of peripheral nerve neurofibromas alone identified 3 subgroups, with group 1 tumors having no CNAs and groups 2&3 enriched for tumors with CDKN2A loss (p < 0.05). In addition, ANNUBP were associated with the loss of CDKN2A (p < 0.05). Neurofibromas with loss of CDKN2A had gene sets associated with H3K27me3 and sarcomas upregulated, while genes associated with neuronal and Schwann cell signature downregulated.
CONCLUSION
The genomic and epigenomic landscape of neurofibromas is poorly understood. We identified that atypical neurofibromas have loss of CDKN2A, suggesting that it is lost early in malignant transformation. The loss of CDKN2A may lead to dysregulation of H3K27me3, and further work is needed to identify the molecular alterations and pathways involved in malignant transformation.