title: Whole-exome sequencing of breast cancer, malignant peripheral nerve sheath tumor and neurofibroma from a patient with neurofibromatosis type 1.
abstract: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by the development of multiple neurofibromas, cafe-au-lait spots, and Lisch nodules. Individuals with NF1 are at increased risk of developing various tumors, such as malignant peripheral nerve sheath tumor (MPNST), pheochromocytoma, leukemia, glioma, rhabdomyosarcoma, and breast cancer. Here, we describe the exome sequencing of breast cancer, MPNST, and neurofibroma from a patient with NF1. We identified a germline mutation in the NF1 gene which resulted in conversion of leucine to proline at amino acid position 847. In addition, we showed independent somatic NF1 mutations in all the three tumors (frameshift insertion in breast cancer (p.A985fs), missense mutation in MPNST (p.G23R), and inframe deletion in dermal neurofibroma (p.L1876del-Inf)), indicating that a second hit in NF1 resulting in the loss of function could be important for tumor formation. Each tumor had a distinct genomic profile with mutually exclusive mutations in different genes. Copy number analysis revealed multiple copy number alterations in the breast cancer and the MPNST, but not the benign neurofibroma. Germline loss of chromosome 6q22.33, which harbors two potential tumor suppressor genes, PTPRK and LAMA2, was also identified; this may increase tumor predisposition further. In the background of NF1 syndrome, although second-hit NF1 mutation is critical in tumorigenesis, different additional mutations are required to drive the formation of different tumors.
authors.affiliation: Division of Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, 169857, Singapore.
authors.forename: John Richard
authors.initials: JR
authors.lastname: McPherson
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Choon-Kiat
authors.initials: CK
authors.lastname: Ong
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Cedric Chuan-Young
authors.initials: CC
authors.lastname: Ng
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Vikneswari
authors.initials: V
authors.lastname: Rajasegaran
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Hong-Lee
authors.initials: HL
authors.lastname: Heng
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Willie Shun-Shing
authors.initials: WS
authors.lastname: Yu
authors.affiliation: Department of General Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore.|Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Benita Kiat-Tee
authors.initials: BK
authors.lastname: Tan
authors.affiliation: Department of General Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Singapore.|Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Preetha
authors.initials: P
authors.lastname: Madhukumar
authors.affiliation: Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Melissa Ching-Ching
authors.initials: MC
authors.lastname: Teo
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.
authors.forename: Joanne
authors.initials: J
authors.lastname: Ngeow
authors.affiliation: Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Diagnostics Tower, Singapore, 169856, Singapore.
authors.forename: Aye-Aye
authors.initials: AA
authors.lastname: Thike
authors.affiliation: Division of Neuroscience and Behavioral Disorders, Duke-National University of Singapore Graduate Medical School, Singapore, 169857, Singapore.
authors.forename: Steven George
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Diagnostics Tower, Singapore, 169856, Singapore.
authors.forename: Puay-Hoon
authors.initials: PH
authors.lastname: Tan
authors.affiliation: Laboratory of Molecular Oncology, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.|Office of Clinical & Academic Faculty Affairs, Duke-National University of Singapore Graduate Medical School, Singapore, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Ann Siew-Gek
authors.initials: AS
authors.lastname: Lee
authors.affiliation: Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.|Laboratory of Cancer Therapeutics, Division of Cancer and Stem Cell Biology, Duke-National University of Singapore Graduate Medical School, 8 College Road, Singapore, 169857, Singapore.|Laboratory of Chromatin Regulation, Cancer Science Institute of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
authors.forename: Bin-Tean
authors.initials: BT
authors.lastname: Teh
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore, 169610, Singapore.|Faculty of Health Sciences, School of Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Yoon-Sim
authors.initials: YS
authors.lastname: Yap
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics*; D056915:DNA Copy Number Variations; D059472:Exome; D005260:Female; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009378:Neoplasms, Multiple Primary / Q000235:genetics*; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009455:Neurofibroma / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics
chemical_list: D025542:Neurofibromin 1
keywords: Breast cancer; neurofibromatosis type 1