title: Mutation landscape in melanoma patients clinical implications of heterogeneity of BRAF mutations.
abstract: BACKGROUND
  The detection of V600E BRAF mutations has fundamental clinical consequences as the treatment option with BRAF inhibitors such as vemurafenib or dabrafenib yields response rates of ~48%. Heterogeneity with respect to BRAF mutation in different metastases has been described in single cases. As this has important implications for the determination of BRAF status and treatment of patients, it is essential to acquire more data.
  
  
  METHODS
  A total of 300 tumour samples from 187 melanoma patients were analysed for BRAF mutations by pyrosequencing. Equivocal results were confirmed by capillary sequencing. Clinical data with respect to melanoma type, tumour site and survival were summarised for 53 patients with multiple analysed tumour samples (2-13 per patient).
  
  
  RESULTS
  BRAF mutations were found in 84 patients (44.9%) and 144 tumour samples (48%) with BRAF mutations in 45.5% of primary tumours and 51.3% of metastases, respectively. In 10 out of 53 patients (18.9%) where multiple samples were analysed results were discordant with respect to mutation findings with wild-type and mutated tumours in the same patient. Mutations did not appear more frequently over the course of disease nor was its occurrence associated with a specific localisation of metastases.
  
  
  CONCLUSIONS
  As heterogeneity with respect to BRAF mutation status is detected in melanoma patients, subsequent testing of initially wild-type patients can yield different results and thus make BRAF inhibitor therapy accessible. The role of heterogeneity in testing and for clinical response to therapy with a BRAF inhibitor needs to be further investigated.
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Heinzerling
authors.forename: M
authors.initials: M
authors.lastname: Baiter
authors.forename: S
authors.initials: S
authors.lastname: Kühnapfel
authors.forename: G
authors.initials: G
authors.lastname: Schuler
authors.forename: P
authors.initials: P
authors.lastname: Keikavoussi
authors.forename: A
authors.initials: A
authors.lastname: Agaimy
authors.forename: F
authors.initials: F
authors.lastname: Kiesewetter
authors.forename: A
authors.initials: A
authors.lastname: Hartmann
authors.forename: R
authors.initials: R
authors.lastname: Schneider-Stock
mesh_terms: D019943:Amino Acid Substitution; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf