The investigators suggested that primary melanomas may contain mixed populations of BRAF-mutant and BRAF WT cells, both able to metastasize, and that resistance to targeted therapies may be mediated by these genetically distinct tumor subclones.51 Data in support of this idea were reported in a study by Colombino et al., who analyzed 291 samples from 132 patients with melanoma.20 Although BRAF mutations were detected in 43% of primary tumors, the rate of BRAF mutations in metastases was 5% greater (48%), consistent with accumulation of de novo genetic abnormalities as melanoma develops. This evidence concerns the gene BRAF and melanoma.