title: Mutated and amplified NRAS in a subset of cutaneous melanocytic lesions with dermal spitzoid morphology: report of two pediatric cases located on the ear.
abstract: Extensive cytogenetic testing is slowly unveiling the complexity of the genomics of melanocytic tumors. NRAS mutations have been the first genetic abnormality described in malignant melanomas. We report the cases of two children, presenting a melanocytic lesion located on the ear. One appeared as a combined dermal clone inside a congenital nevus and the other as a centimetric purely dermal tumor. Both tumors were composed of spindled spitzoid melanocytes with atypical histologic features. aCGH and FISH revealed an amplification of the NRAS gene. Sequencing showed an exon 3 NRAS mutation. In the combined case, the amplification was limited to the spitzoid component, underscoring a possible phenotypic shift induced by the alteration. Similarly an overexpression of CyclinD1 and elevation of ki-67 was found in the spitzoid component confirming a raise in proliferation. Such combination of mutation and copy number increase has been previously reported for the HRAS gene in a subset of Spitz nevi. Further studies must evaluate if mutated NRAS is also amplified in melanomas arising in this clinical setting. These combined alterations could represent an early event ultimately leading to malignancy.
authors.affiliation: Département de Biopathologie, Centre Léon Bérard, Lyon, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Dubruc
authors.forename: Brigitte
authors.initials: B
authors.lastname: Balme
authors.forename: Frédérique
authors.initials: F
authors.lastname: Dijoud
authors.forename: Francois
authors.initials: F
authors.lastname: Disant
authors.forename: Luc
authors.initials: L
authors.lastname: Thomas
authors.forename: Qing
authors.initials: Q
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Pissaloux
authors.forename: Arnaud
authors.initials: A
authors.lastname: de la Fouchardiere
mesh_terms: D002648:Child; D055028:Comparative Genomic Hybridization; D004423:Ear / Q000473:pathology*; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D018332:Nevus, Epithelioid and Spindle Cell / Q000235:genetics* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: NRAS; amplification; congenital nevus; mutation; spitzoid