BRAF mutation by age-decade and body mass index in metastatic melanoma

Background: Melanoma disproportionately affects those under 40yr compared with other solid tumors. Oncogenic BRAF mutations occur at an overall rate of approximately 50%, and are associated with younger age. No study to date has examined decade-specific BRAF mutation rates, a clinically relevant parameter in the era of MAPK-pathway targeting therapy. Obesity is associated with an increased risk of melanoma, however the association of body mass index (BMI) with BRAF mutation status is unknown. We aimed to determine the decade-specific BRAF mutation rate and genotype in metastatic melanoma, and explore its relationship with BMI. Methods: 312 consecutive BRAF-tested patients with unresectable stage IIIC and IV melanoma were analysed. Tumour samples were screened by high-resolution melt curve analysis of BRAF exon 15 with abnormal results confirmed by DNA sequencing. Data were collected to assess demographic and anthropometric variables, and details of the age at metastatic disease diagnosis. Results: 46% of the 312 patients had a BRAF mutation. Of these, 73% were V600E, 19% V600K, and 8% other genotypes. The BRAF mutation rate decreased with increasing age, particularly after age 40 (p<0.001, χ² test). Amongst those with a BRAF mutation, there was a difference in age distribution and BRAF mutation genotype (p=0.05, Kruskal Wallis test). In the subgroup of younger patients (≤40yr), there was a significant difference in BMI between BRAF mutant and wild-type (median BMI 24.3 v 28.8, p=0.03, Mann-Whitney test). Conclusions: In patients with metastatic melanoma, there is an inverse relationship between BRAF mutation rate and age. There is some evidence that BRAF mutation genotype varies with age, with V600E occurring more frequently at younger ages, and V600K at older. BRAF wild-type melanoma may be associated with higher BMI in patients ≤40yr. Phenotypic characterisation of molecular features will have increasing significance as targeted therapies develop, and may direct further research into the mechanisms of oncogenesis in melanoma.