title: The primacy of NF1 loss as the driver of tumorigenesis in neurofibromatosis type 1-associated plexiform neurofibromas.
abstract: Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pemov
authors.affiliation: Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Patidar
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Rockville, MD, USA.
authors.forename: N F
authors.initials: NF
authors.lastname: Hansen
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Sindiri
authors.affiliation: Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Hartley
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Wei
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Rockville, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Elkahloun
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Rockville, MD, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Chandrasekharappa
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: J F
authors.initials: JF
authors.lastname: Boland
authors.affiliation: Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Bass
authors.affiliation: Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Rockville, MD, USA.|NIH Intramural Sequencing Center, National Human Genome Research Institute, Rockville, MD, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Khan
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Widemann
authors.affiliation: Department of Molecular Genetics and Microbiology, UF Genetics Institute, UF Health Cancer Center, University of Florida, Gainesville, FL, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Wallace
authors.affiliation: Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Stewart
mesh_terms: D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004261:DNA Replication; D018628:Gene Dosage; D016147:Genes, Tumor Suppressor; D018095:Germ-Line Mutation; D006801:Humans; D018318:Neurofibroma, Plexiform / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D025542:Neurofibromin 1 / Q000172:deficiency* / Q000235:genetics; D059467:Transcriptome
chemical_list: D025542:Neurofibromin 1