Figure 4. The sequential order of genetic alterations during progression from actinic keratosis to squamous cell carcinoma.

A. Phylogenetic trees, rooted in the germline state, summarize the evolution of four squamous cell carcinomas that evolved from actinic keratoses. See figure S6 for further details on these four cases and figure 3 for a summary of the example case. B. Eight squamous cell carcinomas that evolved from neighboring precursor lesions were identified as described. The stacked bar plot (top panel) indicates the proportion of mutations, recurrently mutated in these eight cases, in the trunk versus branch of phylogenetic trees. The bar plot (lower panel) indicates the number of cases with a mutation in each pathway. Mutations in the p53, Notch, TERT, and Rb pathways tended to occur early, contributing to the formation of actinic keratoses. Mutations affecting the SWI/SNF chromatin remodeling complex or activating the MAPK/PI3K pathways tended to occur later, driving the transition to squamous cell carcinoma. C. The frequency of mutations in select driver genes in normal skin biopsies versus squamous cell carcinoma. Error bars show 95% confidence intervals (Poisson test) with a y=x line included for orientation.