title: Prognostic and predictive values of oncogenic BRAF, NRAS, c-KIT and MITF in cutaneous and mucous melanoma.
abstract: BACKGROUND
  Mutations of BRAF, NRAS and c-KIT oncogenes are preferentially described in certain histological subtypes of melanoma and linked to specific histopathological features. BRAF-, MEK- and KIT-inhibitors led to improvement in overall survival of patients harbouring mutated metastatic melanoma.
  
  
  OBJECTIVE
  To assess the prevalence and types of BRAF, NRAS, c-KIT and MITF mutations in cutaneous and mucous melanoma and to correlate mutation status with clinicopathological features and outcome.
  
  
  METHODS
  Clinicopathological features and mutation status of 108 samples and of 98 consecutive patients were, respectively, assessed in one retrospective and one prospective study. Clinicopathological features were correlated with mutation status and the predictive value of these mutations was studied.
  
  
  RESULTS
  This work identified significant correlations between BRAF mutations and melanoma occurring on non-chronic sun-damaged skin and superficial spreading melanoma (P < 0.05) on one hand, and between NRAS mutations and nodular melanoma (P < 0.05) on the other hand. Younger age (P < 0.05), microscopic (P < 0.05) and macroscopic (P < 0.05) lymphatic involvement at diagnosis of primary melanoma were significantly linked to BRAF mutations. A mutated status was a positive predictive factor of a response to BRAF inhibitors (OR = 3.44). Mutated melanoma showed a significantly (P = 0.038) higher objective response rate to cytotoxic chemotherapy (26.3%) than wild-type tumours (6.7%).
  
  
  CONCLUSIONS
  Clinical and pathological characteristics of the primary melanoma differed between wild-type and BRAF- or NRAS-mutated tumours. Patients with BRAF-mutated tumours were younger at diagnosis of primary melanoma. Patients carrying mutations showed better responses better to specific kinase inhibitors and interestingly also to systemic cytotoxic chemotherapy.
authors.affiliation: Service d'Oncologie Médicale, Centre Eugene Marquis, Rennes, France.|Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.
authors.forename: M
authors.initials: M
authors.lastname: Pracht
authors.affiliation: Gene Expression and Oncogenesis Team, Institut de Génétique et Developement de Rennes, CNRS UMR6290, Rennes, France.|CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Mogha
authors.affiliation: CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|CHU Pontchaillou, Service de Génétique Moléculaire et Génomique des Cancers, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Lespagnol
authors.affiliation: CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|SFR Biosit UMS CNRS 3480/US INSERM 018, Rennes, France.
authors.forename: A
authors.initials: A
authors.lastname: Fautrel
authors.affiliation: Gene Expression and Oncogenesis Team, Institut de Génétique et Developement de Rennes, CNRS UMR6290, Rennes, France.|CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.
authors.forename: N
authors.initials: N
authors.lastname: Mouchet
authors.affiliation: Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.|CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|Service d'Anatomopathologie, CHU Pontchaillou, Rennes, France.
authors.forename: F
authors.initials: F
authors.lastname: Le Gall
authors.affiliation: Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.|Laboratoire d'Anatomopathologie Atalante, Rennes, France.
authors.forename: V
authors.initials: V
authors.lastname: Paumier
authors.affiliation: Service d'Oncologie Médicale, Centre Eugene Marquis, Rennes, France.|Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.
authors.forename: C
authors.initials: C
authors.lastname: Lefeuvre-Plesse
authors.affiliation: CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|Service d'Anatomopathologie, CHU Pontchaillou, Rennes, France.
authors.forename: N
authors.initials: N
authors.lastname: Rioux-Leclerc
authors.affiliation: CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|CHU Pontchaillou, Service de Génétique Moléculaire et Génomique des Cancers, Rennes, France.
authors.forename: J
authors.initials: J
authors.lastname: Mosser
authors.affiliation: CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|Centre d'Investigations Cliniques et Unité de Pharmacologie et de Pharmaco-épidémiologie, Rennes, France.
authors.forename: E
authors.initials: E
authors.lastname: Oger
authors.affiliation: Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.|CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.|CHU Pontchaillou, Service de Dermatologie, Rennes, France.
authors.forename: H
authors.initials: H
authors.lastname: Adamski
authors.affiliation: Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.|Gene Expression and Oncogenesis Team, Institut de Génétique et Developement de Rennes, CNRS UMR6290, Rennes, France.|CHU Pontchaillou, Université Européenne de Bretagne, Rennes, France.
authors.forename: M-D
authors.initials: MD
authors.lastname: Galibert
authors.affiliation: Service d'Oncologie Médicale, Centre Eugene Marquis, Rennes, France.|Brittany Melanoma Network, GRoupe Ouest Mélanome (GROUM), Rennes, France.
authors.forename: T
authors.initials: T
authors.lastname: Lesimple
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics*; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics*; D008875:Middle Aged; D009092:Mucous Membrane; D009154:Mutation; D011379:Prognosis; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000235:genetics*; D055815:Young Adult
chemical_list: C497234:MITF protein, human; D008565:Membrane Proteins; D051739:Microphthalmia-Associated Transcription Factor; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human