Alexander Pemov1, Nancy F Hansen2, Sivasish Sindiri3, Rajesh Patidar3,4, Christine S Higham5,6, Eva Dombi6, Markku M Miettinen7, Patricia Fetsch7, Hilde Brems8, Settara C Chandrasekharappa2, Kristine Jones9, Bin Zhu9, Jun S Wei3, James C Mullikin2,10, Margaret R Wallace11, Javed Khan3, Eric Legius8, Brigitte C Widemann6, Douglas R Stewart1. 1. Clinical Genetics Branch, DCEG, NCI, National Institutes of Health (NIH), Rockville, Maryland, USA. 2. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Rockville, Maryland, USA. 3. Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. 4. Molecular Characterization & Clinical Assay Development Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA. 5. Children's National Medical Center, Washington, DC, USA. 6. Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA. 7. Laboratory of Pathology, NCI, NIH, Bethesda, Maryland, USA. 8. Department of Human Genetics, Catholic University Leuven, Leuven, Belgium. 9. Cancer Genomics Research Laboratory, DCEG, NIH, Rockville, Maryland, USA. 10. NISC, National Human Genome Research Institute, NIH, Rockville, Maryland, USA. 11. Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, Florida, USA.
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. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
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. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2019.
Authors: Srivandana Akshintala; Andrea Baldwin; David J Liewehr; Anne Goodwin; Jaishri O Blakeley; Andrea M Gross; Seth M Steinberg; Eva Dombi; Brigitte C Widemann Journal: Neuro Oncol Date: 2020-09-29 Impact factor: 12.300
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