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Here we describe a spontaneous mutation in the Zdhhc13 (zinc finger, DHHC domain containing 13) gene (also called Hip14l), one of 24 genes encoding palmitoyl acyltransferase (PAT) enzymes in the mouse. This mutation (Zdhhc13luc) was identified as a nonsense base substitution, which results in a premature stop codon that generates a truncated form of the ZDHHC13 protein, representing a potential loss-of-function allele. Homozygous Zdhhc13luc/Zdhhc13luc mice developed generalized hypotrichosis, associated with abnormal hair cycle, epidermal and sebaceous gland hyperplasia, hyperkeratosis, and increased epidermal thickness. Increased keratinocyte proliferation and accelerated transit from basal to more differentiated layers were observed in mutant compared with wild-type (WT) epidermis in untreated skin and after short-term 12-O-tetradecanoyl-phorbol-13-acetate treatment and acute UVB exposure. Interestingly, this epidermal phenotype was associated with constitutive activation of NF-κB (RelA) and increased neutrophil recruitment and elastase activity. Furthermore, tumor multiplicity and malignant progression of papillomas after chemical skin carcinogenesis were significantly higher in mutant mice than WT littermates. To our knowledge, this is the first report of a protective role for PAT in skin carcinogenesis.

To examine the test–retest reliability and validity of self-reported items capturing phenotypic characteristics and sun exposure measures in the baseline survey instrument used for a prospective study of skin cancer and melanoma. Repeatability/validity study conducted among 114 participants randomly selected from the cohort to complete the survey instrument a second time and to undergo a physician skin examination. We calculated intraclass correlation coefficients (ICCs) and kappa (κ) statistics as measures of agreement for continuous and categorical measures, respectively. Measures of phenotypic characteristics showed moderate-to-high agreement (e.g., eye color, κ=0.87; 95% confidence interval [CI]: 0.80, 0.94). Measures of sun exposure had slightly lower estimates of agreement. The repeatability of items relating to medical and family history of skin cancer was high (e.g., the number of skin cancers removed surgically, κw=0.79; 95% CI: 0.71, 0.88). Physician counts of nevi correlated well with categorical measures of self-reported nevus density at the age of 21 years but correlated only modestly with absolute nevus counts conducted by participants (ICC, 0.38; 95% CI: 0.19, 0.54). Our survey instrument demonstrated fair-to-good test–retest reliability for most self-reported risk factors for melanoma, indicating the suitability of these items for developing risk prediction tools in the future.

Cutaneous melanoma causes 55 500 deaths annually. The incidence and mortality rates of the disease differ widely across the globe depending on access to early detection and primary care. Once melanoma has spread, this type of cancer rapidly becomes life-threatening. For more than 40 years, few treatment options were available, and clinical trials during that time were all unsuccessful. Over the past 10 years, increased biological understanding and access to innovative therapeutic substances have transformed advanced melanoma into a new oncological model for treating solid cancers. Treatments that target B-Raf proto-oncogene serine/threonine-kinase (BRAF)V600 (Val600) mutations using selected BRAF inhibitors combined with mitogen-activated protein kinase inhibitors have significantly improved response and overall survival. Furthermore, advanced cutaneous melanoma has developed into a prototype for testing checkpoint-modulating agents, which has increased hope for long-term tumour containment and a potential cure. These expectations have been sustained by clinical success with targeted agents and antibodies that block programmed cell-death protein 1 in locoregional disease, which induces prolongation of relapse-free, distant-metastasis-free, and overall survival times.

Melanoma develops from malignant transformations of the pigment-producing melanocytes. If located in the basal layer of the skin epidermis, melanoma is referred to as cutaneous, which is more frequent. However, as melanocytes are be found in the eyes, ears, gastrointestinal tract, genitalia, urinary system, and meninges, cases of mucosal melanoma or other types (e.g., ocular) may occur. The incidence and morbidity of cutaneous melanoma (cM) are constantly increasing worldwide. Australia and New Zealand are world leaders in this regard with a morbidity rate of 54/100,000 and a mortality rate of 5.6/100,000 for 2015. The aim of this review is to consolidate and present the data related to the aetiology and pathogenesis of cutaneous melanoma, thus rendering them easier to understand. In this article we will discuss these problems and the possible impacts on treatment for this disease.

Squamous-cell and basal-cell carcinomas of the skin are increasing in frequency. Basal-cell carcinomas are responsive to inhibition of the hedgehog pathway; squamous-cell cancers may be responsive to immune checkpoint inhibitors.

Mouse experiments show that ultraviolet radiation can promote tumour metastasis in melanoma by enhancing the expansion of tumour cells on blood vessel surfaces in a process linked to inflammation and requiring neutrophils and the proteins HMGB1 and TLR4. UV-induced melanoma metastasis Ultraviolet (UV) radiation is known to induce melanoma, but whether and how UV irradiation influences the pathogenesis of melanoma indirectly through its effects on the microenvironment is unclear. Here Thomas Tüting and colleagues show that exposing mice to UV radiation in a manner that mimics mild sunburn can promote melanoma metastasis. It does so by inducing the release of the chromatin protein HMGB1 from damaged skin cells. HMGB1 induces inflammation, which in turn promotes angiogenesis and melanoma cell migration and metastasis formation. The authors observe that in this model melanoma, cells spread along the abluminal side of blood vessels in a process called angiotropism, which has been observed in patients, but so far not been mechanistically explained. These findings have important implications for the evaluation of UV exposure as a risk factor for melanoma. Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma 1 . The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established 2 , but how the microenvironmental effects of UV radiation 3 , 4 influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model 5 promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma–endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists 6 . Angiotropism represents a hitherto underappreciated mechanism of metastasis 7 that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

Skin color diversity is the most variable and noticeable phenotypic trait in humans resulting from constitutive pigmentation variability. This paper will review the characterization of skin pigmentation diversity with a focus on the most recent data on the genetic basis of skin pigmentation, and the various methodologies for skin color assessment. Then, melanocyte activity and amount, type and distribution of melanins, which are the main drivers for skin pigmentation, are described. Paracrine regulators of melanocyte microenvironment are also discussed. Skin response to sun exposure is also highly dependent on color diversity. Thus, sensitivity to solar wavelengths is examined in terms of acute effects such as sunburn/erythema or induced-pigmentation but also long-term consequences such as skin cancers, photoageing and pigmentary disorders. More pronounced sun-sensitivity in lighter or darker skin types depending on the detrimental effects and involved wavelengths is reviewed.

Cancer is driven by genomic mutations in ‘cancer driver’ genes, which have essential roles in tumor development. These mutations may be caused by exposure to mutagens in the environment or by endogenous DNA-replication errors in tissue stem cells. Recent observations of abundant mutations, including cancer driver mutations, in histologically normal human tissues suggest that mutations alone are not sufficient for tumor development, thus prompting the question of how single mutant cells give rise to neoplasia. In a concept supported by decades-old data from mouse tumor models, non-mutagenic tumor-promoting agents have been posited to activate the proliferation of dormant mutated cells, thus generating actively growing lesions, with the promotion stage as the rate-limiting step in tumor formation. Non-mutagenic promoting agents, either endogenous or environmental, may therefore have a more important role in human cancer etiology than previously thought. This Perspective explores the concept of tumor promotion and shows how carcinogenesis experiments performed decades ago in mice are remodeling the view of cancer initiation and prevention.

Objectives Firefighters are potentially exposed to a wide range of known and suspected carcinogens through their work. The objectives of this study were to examine the patterns of cancer among Nordic firefighters, and to compare them with the results from previous studies. Methods Data for this study were drawn from a linkage between the census data for 15 million people from the five Nordic countries and their cancer registries for the period 1961–2005. SIR analyses were conducted with the cancer incidence rates for the entire national study populations used as reference rates. Results A total of 16 422 male firefighters were included in the final cohort. A moderate excess risk was seen for all cancer sites combined, (SIR=1.06, 95% CI 1.02 to 1.11). There were statistically significant excesses in the age category of 30–49 years in prostate cancer (SIR=2.59, 95% CI 1.34 to 4.52) and skin melanoma (SIR=1.62, 95% CI 1.14 to 2.23), while there was almost no excess in the older ages. By contrast, an increased risk, mainly in ages of 70 years and higher, was observed for non-melanoma skin cancer (SIR=1.40, 95% CI 1.10 to 1.76), multiple myeloma (SIR=1.69, 95% CI 1.08 to 2.51), adenocarcinoma of the lung (SIR=1.90, 95% CI 1.34 to 2.62), and mesothelioma (SIR=2.59, 95% CI 1.24 to 4.77). By contrast with earlier studies, the incidence of testicular cancer was decreased (SIR=0.51, 95% CI 0.23 to 0.98). Conclusions Some of these associations have been observed previously, and potential exposure to polycyclic aromatic hydrocarbons, asbestos and shift work involving disruption of circadian rhythms may partly explain these results.