<p>Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in <a href="https://www.ncbi.nlm.nih.gov/gene/?term=4763">NF1</a>. NF1 patients have an 8-16% lifetime risk of developing a malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft-tissue sarcoma, often arising from pre-existing benign plexiform neurofibromas (PN) and atypical neurofibromas (ANF). ANF are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. In the first comprehensive genomic analysis of ANF, we performed tumor/normal exome sequencing (ES) of 16 ANFs. In addition, we conducted ES of three MPNSTs, copy-number meta-analysis of 26 ANF and 28 MPNST, and whole transcriptome RNA-seq analysis of five ANF and five MPNST. We identified low mutation burden (median 1, range 0-5) in the exomes of ANF (only <a href="https://www.ncbi.nlm.nih.gov/gene/?term=4763">NF1</a> somatic mutations were recurrent), and frequent deletions of <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1029">CDKN2A</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1030">CDKN2B</a> (69%) and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=6595">SMARCA2</a>(42%) loci. We determined that polycomb repressor complex 2 (PRC2) genes <a href="https://www.ncbi.nlm.nih.gov/gene/?term=8726">EED</a> or <a href="https://www.ncbi.nlm.nih.gov/gene/?term=23512">SUZ12</a> were frequently mutated, deleted or downregulated in MPNST but not in ANF. Our gene expression study revealed upregulated <a href="https://www.ncbi.nlm.nih.gov/gene/?term=4893">NRAS</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=4193">MDM2</a>, <a href="https://www.ncbi.nlm.nih.gov/gene/?term=595">CCND1</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/?term=894">CCND2</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/?term=896">CCND3</a> and <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1019">CDK4</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1021">CDK6</a> in both ANF and MPNST, and overexpression of <a href="https://www.ncbi.nlm.nih.gov/gene/?term=2146">EZH2</a> in MPNST only. We conclude that the PN-ANF transition is primarily driven by the deletion of <a href="https://www.ncbi.nlm.nih.gov/gene/?term=1029">CDKN2A</a>/<a href="https://www.ncbi.nlm.nih.gov/gene/?term=1030">CDKN2B</a> in addition to already present inactivated <a href="https://www.ncbi.nlm.nih.gov/gene/?term=4763">NF1</a>. Further progression from ANF to MPNST likely involves broad chromosomal rearrangements and frequent inactivation of the PRC2 genes, loss of the DNA repair genes, and copy-number increase of signal transduction, cell cycle and pluripotency self-renewal genes.</p>

WES, RNASeq and CNV Analysis of NF1-Associated Atypical Neurofibromas

Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofibromatosis type 1-associated atypical neurofibromas.