title: The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.
abstract: BACKGROUND
  BRAF and NRAS mutations are frequently found in melanoma tumours, and recently developed BRAF-targeted therapies demonstrate significant clinical benefit.
  
  
  OBJECTIVE
  We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.
  
  
  METHODS
  In total, 237 tumours, mostly metastatic lesions, from 203 patients were screened for mutations in exon 15 of BRAF and exon 2 of NRAS using Sanger sequencing. BRAF and NRAS mutation status was analysed in relation to clinical and histopathological characteristics, and outcome.
  
  
  RESULTS
  Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanomas, respectively. We found consistent BRAF and NRAS mutation status in all but one of 27 patients with multiple metastases. BRAF mutation was associated with younger age at primary diagnosis (P = 0.02). Among patients with distant metastatic melanoma, patients with BRAF-mutant tumours without BRAF inhibitor treatment had inferior survival compared with patients with BRAF inhibitor treatment [hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.10-5.01, P = 0.03]. We also observed a trend towards better prognosis for patients with wild-type and NRAS-mutant tumours compared with BRAF V600E-mutant tumours (HR 0.64, 95% CI 0.39-1.04, P = 0.07; and HR 0.76, 95% CI 0.48-1.21, P = 0.25, respectively).
  
  
  CONCLUSIONS
  We were able to confirm the effect of BRAF inhibitor treatment in a single clinical institution. The results suggest further that BRAF mutation is a weak prognostic factor but a strong predictive factor and that BRAF-mutant melanoma might constitute one or more distinct subtypes of the disease with certain aetiology and clinical outcome.
authors.affiliation: Department of Surgery, Lund University, Lund, 22185, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Ekedahl
authors.forename: H
authors.initials: H
authors.lastname: Cirenajwis
authors.forename: K
authors.initials: K
authors.lastname: Harbst
authors.forename: A
authors.initials: A
authors.lastname: Carneiro
authors.forename: K
authors.initials: K
authors.lastname: Nielsen
authors.forename: H
authors.initials: H
authors.lastname: Olsson
authors.forename: L
authors.initials: L
authors.lastname: Lundgren
authors.forename: C
authors.initials: C
authors.lastname: Ingvar
authors.forename: G
authors.initials: G
authors.lastname: Jönsson
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018572:Disease-Free Survival; D005091:Exons; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D011905:Genes, ras; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008565:Membrane Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human