A lack of consensus exists with regards to the relative rates of NRAS and BRAF mutations in the radial (RGP) and vertical (VGP) growth phases of individual melanoma tumors. This study was conducted to test the hypothesis that mutations are acquired with progression from RGP to VGP. Using laser capture microdissection, pure tumor DNA was obtained from 15 in situ melanomas, and from the RGP and VGP of 29 invasive tumors. NRAS exon 2 and BRAF exon 15 DNA were amplified by PCR and sequenced. Mutations were present in 6 of 15 in situ melanomas (40%). Of 29 invasive tumors, 16 exhibited RGP mutations (55.2%); 22 showed VGP mutations (75.9%). Paired RGP/VGP mutation analysis revealed a trend toward discordance in the distribution of mutations, favoring VGP localization (P=0.07). Of 15 samples, 12 with mutations in both phases had an increased proportion of mutated DNA in the VGP, measured on DNA chromatograms (P=0.08). Limitations of this study include a relatively small sample cohort selected for technical reasons from a larger population, presenting the risk of selection bias. These concerns notwithstanding our findings support the hypothesis that NRAS and BRAF mutations increase with tumor progression from superficial to invasive disease. JID JOURNAL CLUB ARTICLE: For questions, answers, and open discussion about this article, please go to http://network.nature.com/group/jidclub.