The rate of growth of primary melanoma is a robust predictor of aggressiveness, but the mutational profile of fast-growing melanomas (FGMM), and its potential to stratify patients at high risk of death, has not been comprehensively studied.

To investigate the epidemiological, clinical and mutational profile of primary cutaneous melanomas with a thickness ≥ 1mm, stratified by rate of growth (ROG).

Observational prospective study. Deep-targeted sequencing of 40 melanoma driver genes on formalin fixed, paraffin embedded primary melanoma samples. Comparison of FGMM (ROG >0.5mm/month) and non-FGMM (ROG≤0.5 mm/month).

Two hundred patients were enrolled among which 70 were FGMM. The relapse free survival was lower in the FGMM group (p=0.014). FGMM had a higher number of predicted deleterious mutations within the 40 genes than non-FGMM (p=0.033). Ulceration (p=0.032), thickness (p=0.006), lower sun exposure (p=0.049), and FGFR2 mutations (p=0.037) were significantly associated with fast growth.

Single-center study, cohort size, potential memory bias, number of investigated genes.

Fast growth is linked to specific tumor biology and environmental factors. Ulceration, thickness and FGFR2 mutations associate with fast growth. Screening for FGFR2 mutations might provide an additional tool to better identify FGMM which are probably good candidates for adjuvant therapies.