Recent research is revealing combinations of disturbed oncogenic and tumor-suppressive signaling pathways by altered or missing genes in skin cancers: mutated PTCH (in the mitogenic Sonic Hedgehog pathway) and mutated p53 tumor suppressor gene in basal cell carcinomas (BCC), possibly an activated mitogenic RAS pathway and mutated p53 in squamous cell carcinomas (SCC), and possibly an activated MET/RAS pathway and inactive p16INK4a tumor suppressor in cutaneous melanomas. UV radiation damages DNA and can give rise to genomic alterations, varying from point mutations to crude chromosomal dislocations. UVB radiation (wavelength band 280–315 nm) is more carcinogenic than UVA radiation (315–400 nm) in experimental induction of SCC. The impact of UVB radiation can be clearly inferred from the characteristic point mutations in p53 found in human SCC and BCC. In contrast to UVB radiation, much of the mutagenic and carcinogenic action of UVA radiation appears to be mediated through reactive oxygen species (ROS). Experiments have shown that UVA1 (340–400 nm) exposure induces SCC largely without the characteristic point mutations in p53. Both UVB and UVA radiation can give rise to ROS-related point mutations (e.g. G to T) and crude genomic alterations (e.g. deletions) which may not be recognized as caused by UV radiation.

Background: The risk of developing cutaneous squamous cell carcinoma (SCC) is markedly increased in organ transplant recipients (OTRs) compared to the normal population. Next to sun exposure, the immunosuppressive regimen is an important risk factor for the development of SCC in OTRs. Various gene mutations (e.g. TP53) and genetic alterations (e.g. loss of CDKN2A, amplification of RAS) have been found in SCCs. The aim of this genome-wide study was to identify pathways and genomic alterations that are consistently involved in the formation of SCCs and their precursor lesions, actinic keratoses (AKs). Methods: To perform the analysis in an isogenic background, RNA and DNA were isolated from SCC, AK and normal (unexposed) epidermis (NS) from each of 13 OTRs. Samples were subjected to genome-wide expression analysis and genome SNP analysis using Illumina’s HumanWG-6 BeadChips and Infinium II HumanHap550 Genotyping BeadChips, respectively. mRNA expression results were verified by quantitative PCR. Results: Hierarchical cluster analysis of mRNA expression profiles showed SCC, AK and NS samples to separate into three distinct groups. Several thousand genes were differentially expressed between epidermis, AK and SCC; most upregulated in SCCs were hyperproliferation related genes and stress markers, such as keratin 6 (KRT6), KRT16 and KRT17. Matching to oncogenic pathways revealed activation of downstream targets of RAS and cMYC in SCCs and of NFκB and TNF already in AKs. In contrast to what has been reported previously, genome-wide SNP analysis showed very few copy number variations in AKs and SCCs, and these variations had no apparent relationship with observed changes in mRNA expression profiles. Conclusion: Vast differences in gene expression profiles exist between SCC, AK and NS from immunosuppressed OTRs. Moreover, several pathways activated in SCCs were already activated in AKs, confirming the assumption that AKs are the precursor lesions of SCCs. Since the drastic changes in gene expression appeared unlinked to specific genomic gains or losses, the causal events driving SCC development require further investigation. Other molecular mechanisms, such as DNA methylation or miRNA alterations, may affect gene expression in SCCs of OTRs. Further study is required to identify the mechanisms of early activation of NFκB and TNF, and to establish whether these pathways offer a feasible target for preventive intervention among OTRs.

As part of an inventory of potential interactions between effects of ozone depletion and climate change, a possible effect of ambient temperature on sun-induced skin cancers was suggested. Mouse experiments had shown that increased room temperature enhanced ultraviolet (UV) radiation-induced carcinogenesis; the effective UV dose was increased by 3–7% per °C. The present investigation was aimed at studying a possible temperature effect on human skin cancer. Existing data on the incidence of human skin cancer were analyzed, as available from two special surveys of non-melanoma skin cancer in the United States. The incidence of non-melanoma skin cancer in the ten regions surveyed not only correlated significantly with the ambient UV dose but also with the average daily maximum temperature in summer. For squamous cell carcinoma the incidence was higher by 5.5% (SE 1.6%) per °C and for basal cell carcinoma by 2.9% (SE 1.4%) per °C. These values correspond to an increase of the effective UV dose by about 2% per °C. Although the precise nature of this correlation with temperature requires further studies, it can be concluded that the temperature rises coming with climate change can indeed amplify the induction of non-melanoma skin cancers by UV radiation in human populations.

Public health guidance recommends limiting sun exposure to sub-sunburn levels, but it is unknown whether these can gain vitamin D (for musculoskeletal health) while avoiding epidermal DNA damage (initiates skin cancer). Well-characterized healthy humans of all skin types (I-VI, lightest to darkest skin) were exposed to a low-dose series of solar simulated UVR of 20%-80% their individual sunburn threshold dose (minimal erythema dose). Significant UVR dose responses were seen for serum 25-hydroxyvitamin D and whole epidermal cyclobutane pyrimidine dimers (CPDs), with as little as 0.2 minimal erythema dose concurrently producing 25-hydroxyvitamin D and CPD. Fractional MEDs generated equivalent levels of whole epidermal CPD and 25-hydroxyvitamin D across all skin types. Crucially, we showed an epidermal gradient of CPD formation strongly correlated with skin darkness (r = 0.74, P < 0.0001), which reflected melanin content and showed increasing protection across the skin types, ranging from darkest skin, where high CPD levels occurred superficially, with none in the germinative basal layer, to lightest skin, where CPD levels were induced evenly across the epidermal depth. People with darker skin can be encouraged to use sub-sunburn UVR-exposure to enhance their vitamin D. In people with lighter skin, basal cell damage occurs concurrent with vitamin D synthesis at exquisitely low UVR levels, providing an explanation for their high skin cancer incidence; greater caution is required.