title: BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.
abstract: OBJECTIVE
  The prevalence of BRAF, NRAS, and p16CDKN2A mutations during melanoma progression remains inconclusive. We investigated the prevalence and distribution of mutations in these genes in different melanoma tissues.
  
  
  METHODS
  In all, 291 tumor tissues from 132 patients with melanoma were screened. Paired samples of primary melanomas (n = 102) and synchronous or asynchronous metastases from the same patients (n = 165) were included. Tissue samples underwent mutation analysis (automated DNA sequencing). Secondary lesions included lymph nodes (n = 84), and skin (n = 36), visceral (n = 25), and brain (n = 44) sites.
  
  
  RESULTS
  BRAF/NRAS mutations were identified in 58% of primary melanomas (43% BRAF; 15% NRAS); 62% in lymph nodes, 61% subcutaneous, 56% visceral, and 70% in brain sites. Mutations were observed in 63% of metastases (48% BRAF; 15% NRAS), a nonsignificant increase in mutation frequency after progression from primary melanoma. Of the paired samples, lymph nodes (93% consistency) and visceral metastases (96% consistency) presented a highly similar distribution of BRAF/NRAS mutations versus primary melanomas, with a significantly less consistent pattern in brain (80%) and skin metastases (75%). This suggests that independent subclones are generated in some patients. p16CDKN2A mutations were identified in 7% and 14% of primary melanomas and metastases, with a low consistency (31%) between secondary and primary tumor samples.
  
  
  CONCLUSIONS
  In the era of targeted therapies, assessment of the spectrum and distribution of alterations in molecular targets among patients with melanoma is needed. Our findings about the prevalence of BRAF/NRAS/p16CDKN2A mutations in paired tumor lesions from patients with melanoma may be useful in the management of this disease.
authors.affiliation: Istituto Chimica Biomolecolare, Consiglio Nazionaledelle Ricerche, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Colombino
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Capone
authors.forename: Amelia
authors.initials: A
authors.lastname: Lissia
authors.forename: Antonio
authors.initials: A
authors.lastname: Cossu
authors.forename: Corrado
authors.initials: C
authors.lastname: Rubino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Giorgi
authors.forename: Daniela
authors.initials: D
authors.lastname: Massi
authors.forename: Ester
authors.initials: E
authors.lastname: Fonsatti
authors.forename: Stefania
authors.initials: S
authors.lastname: Staibano
authors.forename: Oscar
authors.initials: O
authors.lastname: Nappi
authors.forename: Elena
authors.initials: E
authors.lastname: Pagani
authors.forename: Milena
authors.initials: M
authors.lastname: Casula
authors.forename: Antonella
authors.initials: A
authors.lastname: Manca
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Sini
authors.forename: Renato
authors.initials: R
authors.lastname: Franco
authors.forename: Gerardo
authors.initials: G
authors.lastname: Botti
authors.forename: Corrado
authors.initials: C
authors.lastname: Caracò
authors.forename: Nicola
authors.initials: N
authors.lastname: Mozzillo
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieri
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018450:Disease Progression; D005260:Female; D019942:Genes, p16; D011905:Genes, ras; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D059645:Mutation Rate; D009362:Neoplasm Metastasis / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf