Circulating driver gene mutations: What is the impact on melanoma patients' management?

The mutational landscape of melanoma has been progressively defined over the last decade and the central role of somatic muta- tions among specific driver genes (BRAF, NRAS, KIT, NF1) in disease pathogenesis has been well assessed [1, 2]. Although mutations in such genes are mutually exclusive and classify de- fined genotypes (BRAFmut, NRASmut, or KITmut), melanoma is molecularly heterogeneous due to the co-existence of additional recurrent genetic alterations [2]. Melanoma presents a complex biological evolutionary pattern that can move from an initiation phase, somehow induced by ex- posure to extrinsic mutagens (ultraviolet rays) and associated with predisposing genetic conditions, towards the invasive and metastatic phases [3]. The clonal evolution of melanoma may be further driven by the pressure of systemic therapy, with the induction of various resistance mechanisms, which in turn promote relapse and further disease progression [4]. This clonal heterogeneity mostly interferes with response to systemic treat- ments, and is not represented by inter-tumour variations (genetic and phenotypic discrepancies between different tumour and cell types as well as between individuals with the same tumour type), but by intra-tumour changes (occurrence of clones with different genetic and molecular features within the same tumour, which determines a subclonal diversity status) [3].