Cutaneous SCC (cSCC) is the most frequent skin cancer with metastatic potential and can manifest rapidly as a common side effect in patients receiving systemic kinase inhibitors.,Here we use massively parallel exome and targeted level sequencing 132 sporadic cSCC, 39 squamoproliferative lesions and cSCC arising in patients receiving the BRAF inhibitor vemurafenib, as well as 10 normal skin samples to identify significant NOTCH1 mutation as an early event in squamous cell carcinogenesis.,Bisected vemurafenib induced lesions revealed surprising heterogeneity with different activating HRAS and NOTCH1 mutations identified in two halves of the same cSCC suggesting polyclonal origin.,Immunohistochemical analysis using an antibody specific to nuclear NOTCH1 correlates with mutation status in sporadic cSCC and regions of NOTCH1 loss or down-regulation are frequently observed in normal looking skin.,Our data indicate that NOTCH1 acts as a gatekeeper in human cSCC.
Objective To synthesise the literature on indoor tanning and non-melanoma skin cancer.,Design Systematic review and meta-analysis.,Data sources PubMed (1966 to present), Embase (1974 to present), and Web of Science (1898 to present).,Study selection All articles that reported an original effect statistic for indoor tanning and non-melanoma skin cancer were included.,Articles that presented no data, such as review articles and editorials, were excluded, as were articles in languages other than English.,Data extraction Two investigators independently extracted data.,Random effects meta-analysis was used to summarise the relative risk of ever use versus never use of indoor tanning.,Dose-response effects and exposure to indoor tanning during early life were also examined.,The population attributable risk fraction for the United States population was calculated.,Results 12 studies with 9328 cases of non-melanoma skin cancer were included.,Among people who reported ever using indoor tanning compared with those who never used indoor tanning, the summary relative risk for squamous cell carcinoma was 1.67 (95% confidence interval 1.29 to 2.17) and that for basal cell carcinoma was 1.29 (1.08 to 1.53).,No significant heterogeneity existed between studies.,The population attributable risk fraction for the United States was estimated to be 8.2% for squamous cell carcinoma and 3.7% for basal cell carcinoma.,This corresponds to more than 170 000 cases of non-melanoma skin cancer each year attributable to indoor tanning.,On the basis of data from three studies, use of indoor tanning before age 25 was more strongly associated with both squamous cell carcinoma (relative risk 2.02, 0.70 to 5.86) and basal cell carcinoma (1.40, 1.29 to 1.52).,Conclusions Indoor tanning is associated with a significantly increased risk of both basal and squamous cell skin cancer.,The risk is higher with use in early life (<25 years).,This modifiable risk factor may account for hundreds of thousands of cases of non-melanoma skin cancer each year in the United States alone and many more worldwide.,These findings contribute to the growing body of evidence on the harms of indoor tanning and support public health campaigns and regulation to reduce exposure to this carcinogen.