Chronic sun‐damaged (CSD) melanoma represents 10%-20% of cutaneous melanomas and is characterized by infrequent BRAF V600E mutations and high mutational load.,However, the order of genetic events or the extent of intra‐tumor heterogeneity (ITH) in CSDhigh melanoma is still unknown.,Ultra‐deep targeted sequencing of 40 cancer‐associated genes was performed in 72 in situ or invasive CMM, including 23 CSDhigh cases.,In addition, we performed whole exome and RNA sequencing on multiple regions of primary tumor and multiple in‐transit metastases from one CSDhigh melanoma patient.,We found no significant difference in mutation frequency in melanoma‐related genes or in mutational load between in situ and invasive CSDhigh lesions, while this difference was observed in CSDlow lesions.,In addition, increased frequency of BRAF V600K, NF1, and TP53 mutations (p < .01, Fisher's exact test) was found in CSDhigh melanomas.,Sequencing of multiple specimens from one CSDhigh patient revealed strikingly limited ITH with >95% shared mutations.,Our results provide evidence that CSDhigh and CSDlow melanomas are distinct molecular entities that progress via different genetic routes.
In this Review, Rambow et al. use melanoma as a model to present a series of theoretical arguments coupled to recent experimental evidence.,The authors discuss key roles for nongenetic state switching at various steps of the evolution of disease progression and therapy resistance.,An incomplete view of the mechanisms that drive metastasis, the primary cause of cancer-related death, has been a major barrier to development of effective therapeutics and prognostic diagnostics.,Increasing evidence indicates that the interplay between microenvironment, genetic lesions, and cellular plasticity drives the metastatic cascade and resistance to therapies.,Here, using melanoma as a model, we outline the diversity and trajectories of cell states during metastatic dissemination and therapy exposure, and highlight how understanding the magnitude and dynamics of nongenetic reprogramming in space and time at single-cell resolution can be exploited to develop therapeutic strategies that capitalize on nongenetic tumor evolution.