title: Multiple congenital melanocytic nevi and neurocutaneous melanosis are caused by postzygotic mutations in codon 61 of NRAS.
abstract: Congenital melanocytic nevi (CMN) can be associated with neurological abnormalities and an increased risk of melanoma. Mutations in NRAS, BRAF, and Tp53 have been described in individual CMN samples; however, their role in the pathogenesis of multiple CMN within the same subject and development of associated features has not been clear. We hypothesized that a single postzygotic mutation in NRAS could be responsible for multiple CMN in the same individual, as well as for melanocytic and nonmelanocytic central nervous system (CNS) lesions. From 15 patients, 55 samples with multiple CMN were sequenced after site-directed mutagenesis and enzymatic digestion of the wild-type allele. Oncogenic missense mutations in codon 61 of NRAS were found in affected neurological and cutaneous tissues of 12 out of 15 patients, but were absent from unaffected tissues and blood, consistent with NRAS mutation mosaicism. In 10 patients, the mutation was consistently c.181C>A, p.Q61K, and in 2 patients c.182A>G, p.Q61R. All 11 non-melanocytic and melanocytic CNS samples from 5 patients were mutation positive, despite NRAS rarely being reported as mutated in CNS tumors. Loss of heterozygosity was associated with the onset of melanoma in two cases, implying a multistep progression to malignancy. These results suggest that single postzygotic NRAS mutations are responsible for multiple CMN and associated neurological lesions in the majority of cases.
authors: Paediatric Dermatology Department, Great Ormond Street Hospital for Children, London, UK. v.kinsler@ucl.ac.uk
authors: Veronica A
authors: VA
authors: Kinsler
authors: Anna C
authors: AC
authors: Thomas
authors: Miho
authors: M
authors: Ishida
authors: Neil W
authors: NW
authors: Bulstrode
authors: Sam
authors: S
authors: Loughlin
authors: Sandra
authors: S
authors: Hing
authors: Jane
authors: J
authors: Chalker
authors: Kathryn
authors: K
authors: McKenzie
authors: Sayeda
authors: S
authors: Abu-Amero
authors: Olga
authors: O
authors: Slater
authors: Estelle
authors: E
authors: Chanudet
authors: Rodger
authors: R
authors: Palmer
authors: Deborah
authors: D
authors: Morrogh
authors: Philip
authors: P
authors: Stanier
authors: Eugene
authors: E
authors: Healy
authors: Neil J
authors: NJ
authors: Sebire
authors: Gudrun E
authors: GE
authors: Moore
mesh_terms: D000293:Adolescent; D016543:Central Nervous System Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006222:Hamartoma / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008548:Melanosis / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D008577:Meningeal Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D008579:Meningioma / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D009030:Mosaicism; D020125:Mutation, Missense / Q000235:genetics; D020752:Neurocutaneous Syndromes / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D009508:Nevus, Pigmented / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D015995:Prevalence; D012307:Risk Factors; D012878:Skin Neoplasms / Q000151:congenital / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult; D015053:Zygote
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
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