1. NRAS Mutation Is the Sole Recurrent Somatic Mutation in Large Congenital Melanocytic Nevi
- Author
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C Charbel, Selim Aractingi, Gabriel G. Malouf, Jörg Tost, Sarah Guégan, Natacha Kadlub, Xiaoping Su, Aurore Coulomb-L'Hermine, Nizar El-Murr, Alexandre How-Kit, Arnaud Picard, Samia Mourah, and Romain H. Fontaine
- Subjects
Male ,Proto-Oncogene Proteins B-raf ,Risk ,Neuroblastoma RAS viral oncogene homolog ,Pathology ,medicine.medical_specialty ,Genotype ,DNA Mutational Analysis ,Dermatology ,Biology ,medicine.disease_cause ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Biochemistry ,GTP Phosphohydrolases ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Congenital melanocytic nevus ,medicine ,Humans ,Nevus ,Exome ,Child ,Molecular Biology ,Exome sequencing ,Cell Proliferation ,030304 developmental biology ,Nevus, Pigmented ,0303 health sciences ,Mutation ,Melanoma ,Infant ,Membrane Proteins ,Cell Biology ,medicine.disease ,Genes, ras ,Phenotype ,Child, Preschool ,030220 oncology & carcinogenesis ,Melanocytes ,Female - 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.
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