title: NRAS mutation is the sole recurrent somatic mutation in large congenital melanocytic nevi.
abstract: Congenital melanocytic nevus (CMN) is a particular melanocytic in utero proliferation characterized by an increased risk of melanoma transformation during infancy or adulthood. NRAS and BRAF mutations have consistently been reported in CMN samples, but until recently results have been contradictory. We therefore studied a series of large and giant CMNs and compared them with small and medium CMNs using Sanger sequencing, pyrosequencing, high-resolution melting analysis, and mutation enrichment by an enhanced version of ice-COLD-PCR. Large-giant CMNs displayed NRAS mutations in 94.7% of cases (18/19). At that point, the role of additional mutations in CMN pathogenesis had to be investigated. We therefore performed exome sequencing on five specimens of large-giant nevi. The results showed that NRAS mutation was the sole recurrent somatic event found in such melanocytic proliferations. The genetic profile of small-medium CMNs was significantly different, with 70% of cases bearing NRAS mutations and 30% showing BRAF mutations. These findings strongly suggest that NRAS mutations are sufficient to drive melanocytic benign proliferations in utero.
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Charbel
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Romain H
authors.initials: RH
authors.lastname: Fontaine
authors.affiliation: Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Medical Oncology, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
authors.forename: Gabriel G
authors.initials: GG
authors.lastname: Malouf
authors.affiliation: Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Maxillofacial and Plastic Surgery, Hôpital Necker, APHP, Paris, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Picard
authors.affiliation: Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Maxillofacial and Plastic Surgery, Hôpital Necker, APHP, Paris, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Kadlub
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France.
authors.forename: Nizar
authors.initials: N
authors.lastname: El-Murr
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset-CEPH, Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: How-Kit
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Su
authors.affiliation: Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Pathology, Hôpital Trousseau, APHP, Paris, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Coulomb-L'Hermine
authors.affiliation: Laboratory for Functional Genomics, Fondation Jean Dausset-CEPH, Paris, France; Laboratory for Epigenetics and Environment, Centre National de Génotypage, CEA-Institut de Génomique, Evry, France.
authors.forename: Jorg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Laboratory of Pharmacology-Genetics, Hôpital Saint-Louis, APHP, Paris, France.
authors.forename: Samia
authors.initials: S
authors.lastname: Mourah
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université René Descartes-Paris V, Paris, France; Department of Dermatology, Hôpital Cochin, APHP, Paris, France.
authors.forename: Selim
authors.initials: S
authors.lastname: Aractingi
authors.affiliation: Saint Antoine Research Center, U938, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France; Université Pierre et Marie Curie-Paris VI, Paris, France; Department of Dermatology, Hôpital Tenon, APHP, Paris, France. Electronic address: sarah.guegan@tnn.aphp.fr.
authors.forename: Sarah
authors.initials: S
authors.lastname: Guégan
mesh_terms: D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics* / Q000378:metabolism; D011905:Genes, ras; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008544:Melanocytes / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009508:Nevus, Pigmented / Q000151:congenital* / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D012306:Risk
chemical_list: D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human