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  • The estimated annual incidence of skin carcinomas is at least twofold higher than that of all other cancers combined, making these cancers a major burden on the U.S. health care system and a source of significant morbidity and mortality.

  • Most skin cancers arise because of mutations caused by ultraviolet radiation in sunlight, with chemical carcinogens, oncogenic viruses, and other factors contributing to the development of a smaller proportion of tumors.

  • The convergence of evidence from epidemiology, inherited predisposition syndromes, cancer genetics, animal models, and most recently genomics have collectively revealed unprecedented insights into the key causative events that drive the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

  • BCC and SCC display markedly different dependencies on specific pathways: whereas BCC is almost exclusively a Hedgehog pathway—dependent tumor, SCC appears to rely on a more varied set of gene mutations and oncogenic signaling.

  • The accessibility of skin and the ability to model cancer development in animals has been highly useful in identifying the components and functions of key oncogenic signaling pathways, facilitating development of targeted therapeutics, and uncovering general principles of cancer biology.


It was estimated that in 2017, there would be 87,110 new cases of invasive melanoma and 74,680 new cases of melanoma in situ.1 Precise incidence data are not available for basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) because these tumors are not typically reported to cancer registries, but based on Medicare datasets, the total number of nonmelanoma skin cancers in 2006 was estimated at 4,013,890 cases (2,463,567 individuals) and in 2012 at 5,434,193 cases (affecting 3,315,554 individuals).2 Another study, using data from the Medical Expenditure Panel Survey, estimated the number of individuals treated annually for nonmelanoma skin cancers at 3,090,442 (based on data from 2002 to 2006) and 4,301,338 (based on 2007 to 2011 data), with annual treatment costs up from $2.7 to $4.8 billion, respectively.3 The combined incidence of BCC and SCC is thus likely to be at least twofold higher than that of all other cancers combined, which is estimated at 1,688,780 for 2017.1 Only a small fraction of patients with BCC or SCC will die because of their cancer, but the high frequency of these malignancies nonetheless results in an estimated 2000 deaths per year, according to the American Cancer Society, and most cases are SCC. Although much less common than nonmelanoma skin cancer, melanoma has a continually rising death rate now estimated at 9730 per year.1

Although they are rarely lethal, nonmelanoma skin cancers cause considerable cosmetic morbidity because they frequently arise on sun-exposed sites such as the face. Understanding the etiology and pathogenesis of these malignancies is thus a significant public health goal, and development of mechanism-based, nondeforming therapies is urgently needed. The high prevalence of skin tumors, their external location, and well-defined preneoplastic lesions (for SCC and melanoma) all provide an ...

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