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

  1. 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
    Mullikin, James C
    Wallace, Margaret R
    Khan, Javed
    Legius, Eric
    Widemann, Brigitte C
    Stewart, Douglas R

  2. Author Address

    Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA., Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Rockville, MD, USA., Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Molecular Characterization & Clinical Assay Development Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, USA., Children 39;s National Medical Center, Washington, DC, USA., Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA., Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD, USA., Department of Human Genetics, Catholic University Leuven, Leuven, Belgium., Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Rockville, MD, USA., NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Rockville, MD, USA., Dept of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.,
    1. Year: 2019
    2. Date: AUG
    3. Epub Date: 2019 02 05
  2. Journal: Neuro-oncology
    1. 21
    2. 8
    3. Pages: 981-992
  4. Type of Article: Article
  5. ISSN: 1522-8517
  1. Abstract:

    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 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 originating from multiple patients, we performed tumor/normal whole-exome sequencing (WES) of 16 ANFs. In addition, we conducted WES of three MPNSTs, copy-number meta-analysis of 26 ANFs and 28 MPNSTs, and whole transcriptome sequencing analysis of five ANFs and five MPNSTs. 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 or 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. 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, cell cycle and pluripotency self-renewal genes.

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External Sources

  1. View Full Text
  2. DOI: 10.1093/neuonc/noz028
  3. PMID: 30722027
  4. View record in Web of Science®
  5. WOS: 000493069500006
  6. PII : 5307166

Library Notes

  1. Fiscal Year: FY2018-2019
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