title: Oncogene abnormalities in a series of primary melanomas of the sinonasal tract: NRAS mutations and cyclin D1 amplification are more frequent than KIT or BRAF mutations.
abstract: Primary malignant melanoma of sinonasal tract is a rare but severe form of melanoma. We retrospectively analyzed 17 cases and focused on the histologic presentation and the expression of c-Kit, epidermal growth factor receptor (EGFR), cyclin D1/Bcl-1, PS100, and HMB45 and searched for BRAF, NRAS, and KIT mutations that are known to be associated with melanoma subtypes, together with amplifications of KIT, cyclin D1, cyclin-dependent kinase 4, MDM2, and microphthalmia-associated transcription factor using quantitative polymerase chain reaction. In most cases (78%), an in situ component was evidenced. Invasive components were composed of diffuse areas of rhabdoid, epithelioid, or spindle cells and, in most cases, lacked inflammatory reaction, suggesting that an immune escape phenomenon probably develops when the disease progresses. EGFR was rarely and weakly expressed in the in situ component of 2 cases. None of the investigated case showed BRAF V600E, but 1 had a D594G mutation. NRAS mutations in exon 2 (G12D or G12A) were found in 3 cases (18%), and a KIT mutation in exon 11 (L576P), in 1, whereas c-Kit was expressed at the protein level in half of the cases. Amplifications of cyclin D1 were evidenced in 5 cases, confirmed in 3 by fluorescence in situ hybridization, but this was not always correlated with protein expression, found in 8 patients (62.5%), 3 having no significant amplification. In conclusion, primary malignant melanoma of sinonasal tract is not associated with BRAF V600E mutations. Instead, NRAS or KIT mutations and cyclin D1 amplification can be found in a proportion of cases, suggesting that primary malignant melanoma of sinonasal tract is heterogeneous at the molecular level and should not be sensitive to therapeutic approaches aiming at BRAF.
authors.affiliation: Service d'anatomie et cytologie pathologiques, centre hospitalier intercommunal de Créteil, 94000 Créteil, France.
authors.forename: Meriem
authors.initials: M
authors.lastname: Chraybi
authors.forename: Issam
authors.initials: I
authors.lastname: Abd Alsamad
authors.forename: Christiane
authors.initials: C
authors.lastname: Copie-Bergman
authors.forename: Maryse
authors.initials: M
authors.lastname: Baia
authors.forename: Jocelyne
authors.initials: J
authors.lastname: André
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dumaz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ortonne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D019938:Cyclin D1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D010255:Paranasal Sinus Neoplasms / Q000235:genetics* / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012189:Retrospective Studies
chemical_list: C530104:CCND1 protein, human; D004273:DNA, Neoplasm; D008565:Membrane Proteins; D019938:Cyclin D1; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF mutation; CCND1 amplification; Cyclin D1; KIT; NRAS; Primary malignant melanoma of sinonasal tract; Sinonasal melanoma