title: KIT pathway alterations in mucosal melanomas of the vulva and other sites.
abstract: OBJECTIVE
  A significant proportion of mucosal melanomas contain alterations in KIT. The aim of this study was to characterize the pattern of KIT, NRAS, and BRAF mutations in mucosal melanomas at specific sites and to assess activation of the KIT downstream RAF/MEK/extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K)/AKT pathways in mucosal melanoma specimens.
  
  
  METHODS
  Seventy-one primary mucosal melanomas from various sites were studied. Mutation analysis was done by DNA sequencing. Expression of KIT, phosphorylated (p)-ERK, and p-AKT was evaluated by immunohistochemistry.
  
  
  RESULTS
  KIT mutations were detected in 35% (8 of 23) of vulvar, 9% (2 of 22) of anorectal, 7% (1 of 14) of nasal cavity, and 20% (1 of 5) of penile melanomas. No KIT mutations were found in 7 vaginal melanomas. The difference in KIT mutation frequency between vulvar and nonvulvar cases was statistically significant (P = 0.014). The overall frequencies of NRAS and BRAF mutations were 10% and 6%, respectively. Notably, vaginal melanomas showed a NRAS mutation rate of 43%. KIT gene amplification (≥4 copies), as assessed by quantitative real-time PCR, was observed in 19% of cases. KIT expression was associated with KIT mutation status (P < 0.001) and was more common in vulvar than nonvulvar tumors (P = 0.016). Expression of p-ERK and p-AKT was observed in 42% and 59% of tumors, respectively, and occurred irrespective of KIT/NRAS/BRAF mutation status. NRAS mutation was associated with worse overall survival in univariate analysis.
  
  
  CONCLUSIONS
  Results show that KIT mutations are more common in vulvar melanomas than other types of mucosal melanomas and that both the RAF/MEK/ERK and PI3K/AKT pathways are activated in mucosal melanoma specimens.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Katarina
authors.initials: K
authors.lastname: Omholt
authors.forename: Eva
authors.initials: E
authors.lastname: Grafström
authors.forename: Lena
authors.initials: L
authors.lastname: Kanter-Lewensohn
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.forename: Boel K
authors.initials: BK
authors.lastname: Ragnarsson-Olding
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D008875:Middle Aged; D009092:Mucous Membrane / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D016019:Survival Analysis; D014844:Vulva / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*
chemical_list: D019009:Proto-Oncogene Proteins c-kit; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)