Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofobromatosis type1-associated atypical neurofibromas

Pemov, Alexander; Hansen, Nancy F; Sindiri, Sivasish; Patidar, Rajesh; Higham, Christine S; Dombi, Eva; Miettinen, Markku M; Fetsch, Patricia; Brems, Hilde; Chandrasekharappa, Settara; Jones, Kristine; Zhu, Bin; Wei, Jun S; NISC Comparative Sequencing Program,; NCI DCEG Cancer Genomics Research Laboratory,; Mullikin, James C; Wallace, Margaret R; Khan, Javed; Legius, Eric; Widemann, Brigitte C; Stewart, Douglas R

doi:10.1093/neuonc/noz028

Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define pre-malignant neurofobromatosis type1-associated atypical neurofibromas

Author:

Pemov, Alexander

Hansen, Nancy F ; Sindiri, Sivasish ; Patidar, Rajesh ; Higham, Christine S ; Dombi, Eva ; Miettinen, Markku M ; Fetsch, Patricia ; Brems, Hilde ; Chandrasekharappa, Settara ; Jones, Kristine ; Zhu, Bin ; Wei, Jun S ; NISC Comparative Sequencing Program, ; NCI DCEG Cancer Genomics Research Laboratory, ; Mullikin, James C ; Wallace, Margaret R ; Khan, Javed ; Legius, Eric ; Widemann, Brigitte C ; Stewart, Douglas R

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Clinical Neurology, Neurosciences & Neurology, atypical neurofibromas, benign-to-malignant transformation, malignant peripheral nerve sheath tumor, neurofibromatosis type 1, plexiform neurofibromas, NERVE SHEATH TUMORS, SOMATIC POINT MUTATIONS, TOMOGRAPHY FDG-PET, TRANSFORMATION, MORTALITY, SUZ12, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Humans, Mutation, Nerve Sheath Neoplasms, Neurofibroma, Neurofibroma, Plexiform, Neurofibromatosis 1, Neurofibrosarcoma, Transcription Factors, National Intramural Sequencing Center (NISC) Comparative Sequencing Program, National Cancer Institute (NCI) Division of Cancer Epidemiology and Genetics (DCEG) Cancer Genomics Research Laboratory, NISC Comparative Sequencing Program, NCI DCEG Cancer Genomics Research Laboratory, 1109 Neurosciences, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3211 Oncology and carcinogenesis

Abstract:

BACKGROUND: Neurofibromatosis type 1 (NF1) is a tumor-predisposition disorder caused by germline mutations in NF1. 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 preexisting benign plexiform neurofibromas (PNs) and atypical neurofibromas (ANFs). ANFs are distinct from both PN and MPNST, representing an intermediate step in malignant transformation. METHODS: In the first comprehensive genomic analysis of ANF originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of 3 MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of 5 ANFs and 5 MPNSTs. RESULTS: We identified a low number of mutations (median 1, range 0-5) in the exomes of ANFs (only NF1 somatic mutations were recurrent), and frequent deletions of CDKN2A/B (69%) and SMARCA2 (42%). We determined that polycomb repressor complex 2 (PRC2) genes EED and SUZ12 were frequently mutated, deleted, or downregulated in MPNSTs but not in ANFs. Our pilot gene expression study revealed upregulated NRAS, MDM2, CCND1/2/3, and CDK4/6 in ANFs and MPNSTs, and overexpression of EZH2 in MPNSTs only. CONCLUSIONS: The PN-ANF transition is primarily driven by the deletion of CDKN2A/B. 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 and cell-cycle and pluripotency self-renewal genes.