BRAF and NRAS mutations are frequently found in melanoma tumours and recently developed BRAF targeted therapies demonstrate significant clinical benefit.

We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.

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 analyzed in relation to clinical and histopathological characteristics, and outcome.

Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanoma, 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 to patients with BRAF inhibitor treatment (HR=2.35, 95% CI 1.10-5.01, p=0.03). We also observed a trend towards better prognosis for patients with WT and NRAS-mutant tumours compared to BRAFV600E-mutant (HR=0.64, CI 0.96-2.55 p=0.07, and HR=0.76, CI 0.83-2..01 p=0.25, respectively).

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. This article is protected by copyright. All rights reserved.