title: Methylated RASSF1A in malignant peripheral nerve sheath tumors identifies neurofibromatosis type 1 patients with inferior prognosis.
abstract: BACKGROUND
  Malignant peripheral nerve sheath tumor (MPNST) is a rare and highly aggressive disease with no evidence of effect from adjuvant therapy. It is further associated with the hereditary syndrome neurofibromatosis type 1 (NF1). Silencing of the tumor suppressor gene RASSF1A through DNA promoter hypermethylation is known to be involved in cancer development, but its impact in MPNSTs remains unsettled.
  
  
  METHODS
  The RASSF1A promoter was analyzed by methylation-specific PCR in 113 specimens, including 44 NF1-associated MPNSTs, 47 sporadic MPNSTs, 21 benign neurofibromas, and 1 nonneoplastic nerve sheath control.
  
  
  RESULTS
  RASSF1A methylation was found only in the malignant samples (60%) and identified a subgroup among patients with NF1-associated MPNST with a poor prognosis. These patients had a mean 5-year disease-specific survival of 27.3 months (95% CI: 17.2-37.4) versus 47.4 months (95% CI: 37.5-57.2) for NF1 patients with unmethylated promoters, P = 0.014. In multivariate Cox regression analysis, methylated RASSF1A remained an adverse prognostic factor independent of clinical risk factors, P = .013 (hazard ratio: 5.2; 95% CI: 1.4-19.4).
  
  
  CONCLUSIONS
  A considerable number of MPNST samples display hypermethylation of the RASSF1A gene promoter, and for these tumors, this is the first molecular marker that if validated can characterize a subgroup of patients with inferior prognosis, restricted to individuals with NF1.
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Stine A
authors.initials: SA
authors.lastname: Danielsen
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Kolberg
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Maren
authors.initials: M
authors.lastname: Høland
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Bodil
authors.initials: B
authors.lastname: Bjerkehagen
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Kirsten
authors.initials: K
authors.lastname: Sundby Hall
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Eva
authors.initials: E
authors.lastname: van den Berg
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Fredrik
authors.initials: F
authors.lastname: Mertens
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Sigbjørn
authors.initials: S
authors.lastname: Smeland
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Piero
authors.initials: P
authors.lastname: Picci
authors.affiliation: Department of Cancer Prevention, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway (S.A.D., G.E.L., M.K., M.H., R.A.L.); Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (M.H., S.S.); Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway (S.A.D., G.E.L., R.A.L.); Department of Pathology (B.B), Division of Diagnostics and Intervention and Department of Oncology, Division of Cancer, Surgery and Transplantation, Oslo University Hospital-The Norwegian Radium Hospital, Oslo, Norway (K.S.H., S.S.); Department of Medical Genetics, University Hospital of Groningen, The Netherlands (E.v.d.B.); Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden (F.M.); Laboratory of Oncologic Research of the Istituto Ortopedico Rizzoli, Bologna, Italy (P.P.).
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D019175:DNA Methylation; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009442:Neurilemmoma / Q000150:complications / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins
keywords: MPNST; NF1; RASSF1A; methylation; survival