Different melanoma subtypes have distinct evolutionary trajectories, according to a study of 293 cancer-relevant genes in 150 areas of 37 primary melanomas and their adjacent precursor lesions. Researchers found:

• Precursor lesions were initiated by mutations of genes known to activate the mitogen-activated protein kinase pathway.

• Unequivocally benign lesions harbored BRAF V600E mutations exclusively; those categorized as intermediate were enriched for NRAS mutations and additional driver mutations.

• 77% of areas of intermediate lesions and melanomas in situ harbored TERT promoter mutations, indicating that these mutations are selected at an unexpectedly early stage of the neoplastic progression.

• Biallelic inactivation of CDKN2A emerged exclusively in invasive melanomas.

• PTEN and TP53 mutations were found only in advanced primary melanomas.

• Point-mutation burden increased from benign through intermediate lesions to melanoma, with a strong signature of ultraviolet radiation effects detectable at all stages.

• Copy-number alterations became prevalent only in invasive melanomas.

• Tumor heterogeneity became apparent as genetically distinct subpopulations while melanomas progressed.

Citation: Shain AH, Yeh I, Kovalyshyn I, et al. The genetic evolution of melanoma from precursor lesions. N Engl J Med. 2015;373(20):1926-1936. doi: 10.1056/NEJMoa1502583.