title: Primary melanoma of the CNS in children is driven by congenital expression of oncogenic NRAS in melanocytes.
abstract: NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.
  
  
  CONCLUSIONS
  We show that the acquisition of NRAS mutations in melanocytes during embryogenesis is a risk factor for early-onset melanoma of the CNS. We have developed a powerful mouse model to study this rare but devastating childhood disease, and to develop therapeutic approaches for its treatment.
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Malin
authors.initials: M
authors.lastname: Pedersen
authors.affiliation: Department of Pathology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands.
authors.forename: Heidi V N
authors.initials: HVN
authors.lastname: Küsters-Vandevelde
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Amaya
authors.initials: A
authors.lastname: Viros
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9100, 6500 HB Nijmegen, The Netherlands.
authors.forename: Patricia J T A
authors.initials: PJTA
authors.lastname: Groenen
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, London, SW3 6JB, UK.
authors.forename: Berta
authors.initials: B
authors.lastname: Sanchez-Laorden
authors.affiliation: Department of Neurology, Reinier De Graaf Hospital, PO Box 5011, 2600 GA Delft, The Netherlands.
authors.forename: Jacobus H
authors.initials: JH
authors.lastname: Gilhuis
authors.affiliation: Department of Pathology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands.
authors.forename: Ilse A
authors.initials: IA
authors.lastname: van Engen-van Grunsven
authors.affiliation: Department of Neurology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands.
authors.forename: Willy
authors.initials: W
authors.lastname: Renier
authors.affiliation: Department of Neurology, Radboud University Nijmegen Medical Centre, PO Box 9100, 6500 HB Nijmegen, The Netherlands.
authors.forename: Jolanda
authors.initials: J
authors.lastname: Schieving
authors.affiliation: Gene and Oncogene Targeting Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Ion
authors.initials: I
authors.lastname: Niculescu-Duvaz
authors.affiliation: Gene and Oncogene Targeting Team, Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Surrey SM2 5NG, UK.
authors.forename: Caroline J
authors.initials: CJ
authors.lastname: Springer
authors.affiliation: Department of Pathology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands.
authors.forename: Benno
authors.initials: B
authors.lastname: Küsters
authors.affiliation: Department of Pathology, Canisius Wilhelmina Hospital, PO Box 9015, 6500 GS Nijmegen, The Netherlands.|Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9100, 6500 HB Nijmegen, The Netherlands.|Department of Pathology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Pieter
authors.initials: P
authors.lastname: Wesseling
authors.affiliation: Department of Pathology, Radboud University Nijmegen Medical Centre, PO Box 9100, 6500 HB Nijmegen, The Netherlands.
authors.forename: Willeke A M
authors.initials: WAM
authors.lastname: Blokx
authors.affiliation: Signal Transduction Team, The Institute of Cancer Research, London, SW3 6JB, UK.|Molecular Oncology Group, CRUK Manchester Institute, University of Manchester, Manchester M20 4BX, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Marais
mesh_terms: D000818:Animals; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000378:metabolism*; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL