title: Mutational status of naevus-associated melanomas.
abstract: BACKGROUND
  The origin of melanoma has always been a debated subject, as well as the role of adjacent melanocytic naevi. Epidemiological and histopathological studies point to melanomas arising either de novo or from a naevus.
  
  
  OBJECTIVE
  To evaluate the presence of mutations in genes from well-known melanomagenesis pathways in a large series of naevus-associated melanomas.
  
  
  METHODS
  Sixty-one melanomas found in association with a pre-existing naevus were microdissected, after careful selection of cell subpopulations, and submitted to Sanger sequencing of the BRAF, NRAS, c-KIT, PPP6C, STK19 and RAC1 genes. Each gene was evaluated twice in all samples by sequencing or by sequencing and another confirmation method, allele-specific fluorescent polymerase chain reaction (PCR) and capillary electrophoresis detection or by SNaPshot analysis. Only mutations confirmed via two different molecular methods or twice by sequencing were considered positive.
  
  
  RESULTS
  The majority of cases presented concordance of mutational status between melanoma and the associated naevus for all six genes (40 of 60; 66.7%). Nine cases presented concomitant BRAF and NRAS mutations, including one case in which both the melanoma and the adjacent naevus harboured V600E and Q61K double mutations. In two cases, both melanoma and associated naevus located on acral sites were BRAF mutated, including an acral lentiginous melanoma.
  
  
  CONCLUSIONS
  To our knowledge this is the largest naevus-associated melanoma series evaluated molecularly. The majority of melanomas and adjacent naevi in our sample share the same mutational profile, corroborating the theory that the adjacent naevus and melanoma are clonally related and that the melanoma originated within a naevus.
authors: Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.|Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.
authors: D
authors: D
authors: Shitara
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
authors: G
authors: G
authors: Tell-Martí
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
authors: C
authors: C
authors: Badenas
authors: Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.|Department of Pathology, Federal University of São Paulo, São Paulo, Brazil.
authors: M M S S
authors: MM
authors: Enokihara
authors: Melanoma Unit, Pathology Service, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.
authors: L
authors: L
authors: Alós
authors: Melanoma Unit, Pathology Service, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.
authors: A B
authors: AB
authors: Larque
authors: Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.|Department of Pathology, Federal University of São Paulo, São Paulo, Brazil.
authors: N
authors: N
authors: Michalany
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.
authors: J A
authors: JA
authors: Puig-Butille
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors: C
authors: C
authors: Carrera
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors: J
authors: J
authors: Malvehy
authors: Melanoma Unit, Dermatology, Biochemistry and Molecular Genetics Departments, Hospital Clinic of Barcelona, IDIBAPS, Barcelona, Spain.|CIBER de Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain.|University of Barcelona, Barcelona, Spain.
authors: S
authors: S
authors: Puig
authors: Department of Dermatology, Federal University of São Paulo, São Paulo, Brazil.
authors: E
authors: E
authors: Bagatin
mesh_terms: D020558:GTP Phosphohydrolases / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009508:Nevus, Pigmented / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D012878:Skin Neoplasms / Q000235:genetics*; D020830:rac1 GTP-Binding Protein / Q000235:genetics
chemical_list: D008565:Membrane Proteins; D009687:Nuclear Proteins; D019009:Proto-Oncogene Proteins c-kit; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; C087996:STK19 protein, human; D010749:Phosphoprotein Phosphatases; C106079:protein phosphatase 6; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D020830:rac1 GTP-Binding Protein