We identified 44 AK SMGs, including many classical tumor suppressor genes (TP53, NOTCH1, NOTCH2, and FAT1), that are consistently mutated in cSCC, but importantly, these genes are also mutated at low levels and under strong positive selection in physiologically normal sun-exposed skin (Martincorena et al., 2015). This evidence concerns the gene NOTCH2 and skin squamous cell carcinoma.