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Cong-Li Jia,1 Fu Yang,2 Rui-Ning Li3 1Weifang Medical College, Weifang, Shandong, People’s Republic of China; 2Department of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, People’s Republic of China; 3Second Clinical Medical College, Lanzhou University, Lanzhou, Gansu, People’s Republic of ChinaCorrespondence: Fu YangDepartment of Hepatobiliary Surgery, First Affiliated Hospital of Kunming Medical University, No. 295, Xi Chang Road, Kunming, Yunnan, 650032, People’s Republic of ChinaTel +86 13888428338Email dediracy@163.comPurpose: To identify the potential differential genes between primary and metastatic melanoma, screen out immune-related genes in core genes and analyze their immune correlation, thus searching for the early diagnostic biomarkers of cutaneous malignant melanoma (CMM) and the targets of curbing metastasis.Materials and Methods: We analyzed two microarray datasets (GSE8401 and GSE46517) derived from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) between primary and metastatic melanoma were screened out using the GEO2R tool. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed to identify the functions and pathways of DEGs. We analyzed protein–protein interaction of these DEGs based on the Search Tool for the Retrieval of Interacting Genes database and showed by Cytoscape software. In addition, the online Gene Expression Profiling Interactive Analysis tool (GEPIA) was used to analyze the prognostic value of hub genes expressed in metastatic melanoma patients. Immune-related genes in hub genes were screened and further analyzed.Results: A total of 178 upregulated DEGs and 4 downregulated DEGs were identified. 23 terms and 4 pathways were confirmed related to metastatic melanoma. Ten hub genes with a high degree of connectivity were found. Overexpression of three hub genes (DSG1, FLG, PKP1) (P< 0.01) was associated with metastasis and poor prognosis of CMM. Among them, the patients with overexpression of PKP1 suffered shorter survival. In addition, 2 immune-related genes (EGFR and CDH1) in hub genes were screened out and both of them were related to anti-tumor immunity, although their expression level did not affect the overall survival of CMM patients significantly.Conclusion: Our study suggests that DSG1, FLG and PKP1 were overexpressed in metastatic melanoma compared with primary melanoma, and overexpression of these three genes was an unfavorable prognostic factor ifor CMM patients, which may indicate that they are associated with promoting metastasis of malignant melanoma. EGFR and CDH1 play a crucial role in anti-tumor immunity for CMM. Further research is needed to explore the value of these genes in the inhibition of metastasis and treatment of CMM.Keywords: cutaneous malignant melanoma, metastasis, genes, PKP1, DSG1, FLG, CDH1, EGFR

Post-therapeutic relapse, poor survival rates and increasing incidence justify the search for novel therapeutic targets and strategies in cutaneous malignant melanoma (CMM). Within this context, a potential oncogenic role for TrkA in CMM is suggested by reports of NTRK1 amplification, enhanced TrkA expression and intracellular TrkA activation associated with poor prognosis. TrkA, however, exhibits tumour-suppressing properties in melanoma cell lines and has recently been reported not to be associated with CMM progression. To better understand these contradictions, we present the first analysis of potential oncogenic alternative TrkA mRNA splicing, associated with TrkA immunoreactivity, in CMMs, and compare the behaviour of fully spliced TrkA and the alternative TrkAIII splice variant in BRAF(V600E)-mutated A375 melanoma cells. Alternative TrkA splicing in CMMs was associated with unfolded protein response (UPR) activation. Of the several alternative TrkA mRNA splice variants detected, TrkAIII was the only variant with an open reading frame and, therefore, oncogenic potential. TrkAIII expression was more frequent in metastatic CMMs, predominated over fully spliced TrkA mRNA expression in ≈50% and was invariably linked to intracellular phosphorylated TrkA immunoreactivity. Phosphorylated TrkA species resembling TrkAIII were also detected in metastatic CMM extracts. In A375 cells, reductive stress induced UPR activation and promoted TrkAIII expression and, in transient transfectants, promoted TrkAIII and Akt phosphorylation, enhancing resistance to reductive stress-induced death, which was prevented by lestaurtinib and entrectinib. In contrast, fully spliced TrkA was dysfunctional in A375 cells. The data identify fully spliced TrkA dysfunction as a novel mechanism for reducing melanoma suppression, support a causal relationship between reductive stress, UPR activation, alternative TrkAIII splicing and TrkAIII activation and characterise a targetable oncogenic pro-survival role for TrkAIII in CMM.

Cutaneous malignant melanoma (CMM) is responsible for ≥1/2 of skin cancer-related mortalities. The aberrant expression of long non-coding RNAs (lncRNAs) has been associated with the development of CMM. However, to the best of our knowledge, the role of the lncRNA TINCR ubiquitin domain containing (TINCR) in CMM has not been previously investigated, and thus, the current study aimed to evaluate this in vitro and in vivo. Reverse transcription-quantitative PCR (RT-qPCR) was used to analyze microRNA (miR)-424-5p expression, and RT-qPCR and western blotting were used to measure TINCR, large tumor suppressor kinase 1 (LATS1), cellular communication network factor 2 (CTGF), cellular communication network factor 1 (CCN1) and AXL receptor tyrosine kinase (AXL) mRNA and protein expression levels, respectively. Cell Counting Kit-8, flow cytometry and Transwell assays were used to detect the proliferation, apoptosis and invasion of CMM cell lines, respectively. The binding sites between TINCR and miR-424-5p were predicted using the miRDB database. A dual luciferase reporter assay and RT-qPCR were used to identify the relationship between TINCR and miR-424-5p in CMM cell lines. The bioinformatics analysis revealed that TINCR was one of the most significantly downregulated lncRNAs in CMM, and advanced stage CMM tissues showed the greatest decrease in TINCR expression. Moreover, in the collected CMM tissues and tested cell lines of the current study, TINCR expression was found to be downregulated compared with the respective controls. Notably, TINCR overexpression inhibited the expression levels of CTGF, CCN1 and AXL, decreased the proliferation and invasion, and induced the apoptosis of CMM cell lines. In addition, a mutual binding association was identified between miR-424-5p and TINCR in CMM cells. LATS1, a target of miR-424-5p, was found to be positively regulated by TINCR. TINCR activated Hippo signaling and repressed the activity of Yes 1 associated transcriptional regulator by regulating LATS1 expression, while LATS1 knockdown reversed the effect of TINCR overexpression on CMM cells. Collectively, the findings of the present study suggested that TINCR may attenuate the progression of CMM by regulating the miR-424-5p/LATS1 signaling axis. These results indicated that TINCR may play a tumor suppressive role in CMM.

Multiple myeloma is a plasma cell dyscrasia characterized by abnormal bone marrow clonal plasma cells, histological confirmation of plasmacytoma, monoclonal protein in serum or urine, and evidence of end-organ damage. Organ involvement in multiple myeloma manifests as CRAB (hyperCalcemia, Renal insufficiency, Anemia, lytic Bone lesions). Cutaneous complications in multiple myeloma have been reported in many different phenotypes such as cryoglobulinemia rash, bruising, amyloid deposition, and squamous cell carcinoma. However, cutaneous metastasis of multiple myeloma is very rare with fewer than 100 cases described in the literature so far. Here, we present a case of biopsy-confirmed primary cutaneous multiple myeloma. Our case has other less common features of multiple myeloma such as renal amyloidosis and a coexisting malignant melanoma. This case report describes a unique presentation of multiple myeloma to understand the disease better.

Background For patients with sentinel lymph node (SLN)-positive cutaneous melanoma, the Second Multicenter Selective Lymphadenectomy trial demonstrated equivalent disease-specific survival (DSS) with active surveillance using nodal ultrasound versus completion lymph node dissection (CLND). Adoption and outcomes of active surveillance in clinical practice and in adjuvant therapy recipients are unknown.Methods In a retrospective cohort of SLN-positive adults treated at 21 institutions in Australia, Europe, and the United States from June 2017 to November 2019, the authors evaluated the impact of active surveillance and adjuvant therapy on all-site recurrence-free survival (RFS), isolated nodal RFS, distant metastasis-free survival (DMFS), and DSS using Kaplan-Meier curves and Cox proportional hazard models.Results Among 6347 SLN biopsies, 1154 (18%) were positive and had initial negative distant staging. In total, 965 patients (84%) received active surveillance, 189 (16%) underwent CLND. Four hundred thirty-nine patients received adjuvant therapy (surveillance, 38%; CLND, 39%), with the majority (83%) receiving anti-PD-1 immunotherapy. After a median follow-up of 11 months, 220 patients developed recurrent disease (surveillance, 19%; CLND, 22%), and 24 died of melanoma (surveillance, 2%; CLND, 4%). Sixty-eight patients had an isolated nodal recurrence (surveillance, 6%; CLND, 4%). In patients who received adjuvant treatment without undergoing prior CLND, all isolated nodal recurrences were resectable. On risk-adjusted multivariable analyses, CLND was associated with improved isolated nodal RFS (hazard ratio [HR], 0.36; 95% CI, 0.15-0.88), but not all-site RFS (HR, 0.68; 95% CI, 0.45-1.02). Adjuvant therapy improved all-site RFS (HR, 0.52; 95% CI, 0.47-0.57). DSS and DMFS did not differ by nodal management or adjuvant treatment.Conclusions Active surveillance has been adopted for most SLN-positive patients. At initial assessment, real-world outcomes align with randomized trial findings, including in adjuvant therapy recipients.Lay SummaryFor patients with melanoma of the skin and microscopic spread to lymph nodes, monitoring with ultrasound is an alternative to surgically removing the remaining lymph nodes.The authors studied adoption and real-world outcomes of ultrasound monitoring in over 1000 patients treated at 21 centers worldwide, finding that most patients now have ultrasounds instead of surgery.Although slightly more patients have cancer return in the lymph nodes with this strategy, typically, it can be removed with delayed surgery.Compared with up-front surgery, ultrasound monitoring results in the same overall risk of melanoma coming back at any location or of dying from melanoma.

Supplemental Digital Content is available in the text., Introduction of targeted therapy in the treatment of metastatic cutaneous malignant melanoma (CMM) has improved clinical outcome during the last years. However, only in a subset of the CMM patients, this will lead to long-term effects. CEBPB is a transcription factor that has been implicated in various physiological and pathological processes, including cancer development. We have investigated its prognostic impact on CMM and unexpectedly found that higher CEBPB mRNA levels correlated with a longer overall survival. Furthermore, in a small cohort of patients with metastatic CMM treated with BRAF-inhibitors, higher levels of CEBPB mRNA expression in the tumor cells prior treatment correlated to a longer progression-free survival. We have characterized an overlapping antisense transcript, CEBPB-AS1, with the aim to investigate the regulation of CEBPB expression in CMM and its impact on BRAF-inhibitor sensitivity. We demonstrated that silencing of CEBPB-AS1 resulted in epigenetic modifications in the CEBPB promoter and in increased CEBPB mRNA and protein levels, inhibited proliferation and partially resensitized BRAF-inhibitor resistant CMM cells to this drug-induced apoptosis. Our data suggest that targeting CEBPB-AS1 may represent a valuable tool to sensitize CMM cells to the BRAF-inhibitor-based therapies.

Talimogene laherparepvec is a genetically modified herpes simplex virus type 1–based oncolytic immunotherapy for the local treatment of unresectable subcutaneous and nodal tumors in patients with melanoma recurrent after initial surgery. We report on two patients with melanoma who, after progression on numerous systemic therapies, derived clinical benefit from talimogene laherparepvec in an expanded-access protocol (ClinicalTrials.gov, NCT02147951). Intralesional talimogene laherparepvec (day 1, ≤4 ml 106 PFU/ml; after 3 weeks, ≤4 ml 108 PFU/ml every 2 weeks) was administered until complete response, no injectable tumors, progressive disease, or intolerance occurred. Patient 1 was 71 years old, had stage IIIB disease, and had previously received granulocyte–macrophage colony-stimulating factor, vemurafenib, metformin, ipilimumab, dabrafenib, trametinib, and pembrolizumab. Patient 2 was 45 years old, had stage IIIC disease, and had previously received nivolumab/ipilimumab combination therapy. There were marked reductions in the number and size of melanoma lesions during treatment with talimogene laherparepvec. Both patients experienced mild-to-moderate nausea and vomiting, which were managed using ondansetron, metoclopramide, and pantoprazole. Both patients completed treatment with talimogene laherparepvec in the expanded-access protocol on 24 November 2015, but received talimogene laherparepvec in clinical practice. Patient 1 continues to receive therapy (>60 weeks); patient 2 experienced a complete response at 23 weeks. Immunohistochemistry of a biopsied dermal metastasis from patient 1 showed a marked infiltration of CD4+ and CD8+ T cells after 1 year of treatment. Talimogene laherparepvec was active in patients with advanced melanoma with disease progression following multiple previous systemic therapies; no new safety signals were identified.

Background: The current vitamin D deficiency epidemic is accompanied by an increase in endemic skin cancer. There are still multiple controversies. This review aims to give practical recommendations regarding vitamin D among people at risk or with a personal history of skin cancer. Methods: Narrative review including human research articles published between 2011 and 2021, elaborated bearing in mind an epidemiological, patient-centered approach. Results: Ultraviolet (UV) exposure (neither artificial nor natural) is not the ideal source to synthesize vitamin D. There is conflicting epidemiological evidence regarding vitamin D, non-melanoma skin cancer (NMSC), and cutaneous melanoma (CMM), confounded by the effect of sun exposure and other factors. Conclusions: Current evidence is controversial, and there are no widely applicable strategies. We propose three practical recommendations. Firstly, sun protection recommendations should be kept among people at risk or with a personal history of skin cancer. Secondly, vitamin D should preferably be sourced through diet. In patients with melanoma or at risk of cutaneous cancer, serum vitamin D checks are warranted to detect and avoid its insufficiency.

Dysregulation of the kynurenine pathway has been regarded as a mechanism of tumor immune escape by the enzymatic activity of indoleamine 2, 3 dioxygenase and kynurenine production. However, the immune-modulatory properties of other kynurenine metabolites such as kynurenic acid, 3-hydroxykynurenine, and anthranilic acid are poorly understood. In this study, plasma from patients diagnosed with metastatic cutaneous malignant melanoma (CMM) was obtained before (PRE) and during treatment (TRM) with inhibitors of mitogen-activated protein kinase pathway (MAPKIs). Immuno-oncology related protein profile and kynurenine metabolites were analyzed by proximity extension assay (PEA) and LC/MS-MS, respectively. Correlation network analyses of the data derived from PEA and LC/MS-MS identified a set of proteins that modulate the differentiation of Th1 cells, which is linked to 3-hydroxykynurenine levels. Moreover, MAPKIs treatments are associated with alteration of 3-hydroxykynurenine and 3hydroxyanthranilic acid (3HAA) concentrations and led to higher “CXCL11,” and “KLRD1” expression that are involved in T and NK cells activation. These findings imply that the kynurenine pathway is pathologically relevant in patients with CMM.

Aims: MicroRNA-186 (miR-186) has been shown to be involved in various types of cancer. The purpose of this study was to investigate the expression level and functional role of miR-186 in human cutaneous malignant melanoma cells. Subjects and Methods: Expression of miR-186 was analyzed in human cutaneous malignant melanoma (CMM) cell lines SK-MEL-1, G-361, A375 and A875, and human normal epidermal melanocytes cell line HEMn-LP by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Additionally, the functional role of miR-186 on melanoma cells was investigated by transfection of miR-186 mimic followed by analyses of cell proliferation, apoptosis, and metastasis. Results: We found that the expression levels of miR-186 were decreased in CMM cell lines compared with normal epidermal melanocytes cell line. Moreover, overexpression of miR-186 inhibited cells proliferation through abrogating the G1–S transition, and reduced cells migration and invasion. Conclusions: Our findings suggested that miR-186 exhibit an inhibitory effect on CMM cell proliferation, migration, and invasion; thus, may serve as a potential therapeutic target for human CMM intervention.

Background Skin cancers are the most common cancers around the world. Cutaneous malignant melanoma (CMM) is the malignancy of melanocytes that are mainly located in the skin and mucous membranes. Objective This study tried to evaluate the incidence and mean survival time of cutaneous malignant melanoma (CMM) in Yazd, Iran. It seems that the epidemiology and clinical aspects of CMM in Iran are different from those in other parts of the world; also due to the limited and scattered studies there isn't lot in the literature regarding CMM in Iran. Materials and Methods This study used data obtained from the cancer registry center in the province of Yazd for a period of 21 years (1988 – 2008). Population and statistical data were gathered from “National Organization for Civil Registration”. Population-based data were analyzed, focusing on the incidence and mean survival time over this 21 year period. Results The mean incidence rate for CMM in Yazd-Iran between 1988 and 2008 was 0.40 per 100,000 for males and 0.27 per 100,000 for females per year, and the incidence of CMM was relatively constant during this period of time. The mean survival rates for women were better than men (80.5% and 76.3% respectively). Conclusions CMM in Yazd is a low-incidence skin tumor that shows a relatively fixed incidence between 1988 and 2008, Higher incidences of CMM were found in sun-exposed areas (especially head and neck areas), with more incidence in men. Skin cancers and CMM incidence in Iran is lower than western countries, most probably due to geographical zone, genetic factors, skin type, society-related customs including clothing styles.

Apoptosis is central to the biology of cutaneous malignant melanoma (CMM). The leucine zipper, down regulated in cancer 1 (LDOC-1) gene, is known to be a regulator of the nuclear factor kappa B (NF-kB) through inhibition of the same NF-kB. The poly (ADP-ribose) polymerase-1 (PARP1) gene plays an important role for the efficient maintenance of genome integrity. PARP-1 protein is required for the apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus. We report here two interesting cases of family melanoma, a father and son 84 and 40 years old, respectively. The histological evaluation of the lesions of both men revealed diffused superficial melanoma with epithelioid cells. We evaluated the differential expression of LDOC-1 and PARP-1 mRNA in peripheral blood leukocytes of both the father and son. We found that both LDOC-1 and PARP-1 genes were down-regulated in both patients compared with those of controls. These data suggest that low levels of expression of LDOC-1 and PARP-1 mRNA may be associated with familial melanoma.

Incidence rates of skin cancer increase with decreasing latitude in Norway, as in many other countries with white populations. The latitudinal trends of the incidence rates of skin cancer were studied and compared with data for vitamin D-induced by UV and for vitamin D intake. The north-south gradient for CMM incidence rates on sun exposed skin is much smaller than those for BCC and SCC, and that for BCC is smaller than that for SCC. This indicates that SCC and BCC are mainly due to solar UVB, while UVA may play a significant role for CMM and a smaller role for BCC, since the north-south gradient of annual UVB fluences is larger than that of UVA fluences. However, there is an inverse latitudinal gradient of skin cancer in central Europe. This is probably due to a gradient of skin color, since white skin is an important determinant of increased risk of skin cancer. The role of vitamin D for skin cancer risk is difficult to evaluate, since serum levels of 25-hydroxyvitamin D, as well as vitamin D intakes, are widely different from country to country. Still, epidemiological evidence indicates a role: for melanomas arising on non-sun exposed body localizations (uveal melanomas, melanomas arising in the vulva and perianal/anorectal regions) there appears to be no latitudinal gradient, or, a negative gradient, i.e., increasing rates with decreasing latitude as would be expected if UV-generated vitamin D plays a protective role. Both skin cancer risk and vitamin D photosynthesis decrease with increasing skin darkness.

Cutaneous malignant melanoma is the most lethal form of skin cancer and an increasingly common disease worldwide. It remains one of the most treatment-refractory malignancies. The current treatment options for patients with metastatic melanoma are limited and in most cases non-curative. This review focuses on conventional chemotherapeutic drugs for melanoma treatment, by a single or combinational agent approach, but also summarizes some potential novel phytoagents discovered from dietary vegetables or traditional herbal medicines as alternative options or future medicine for melanoma prevention. We explore the mode of actions of these natural phytoagents against metastatic melanoma.

We recently reported an association between low DNA repair capacity, measured through the host-cell reactivation assay, and melanoma risk in subjects with dysplastic naevi or low tanning ability. We investigated the genetic basis for these findings by analysing the Asp312Asn and Lys751Gln polymorphisms of the XPD (ERCC2) DNA repair gene in the same subjects. Similar to our previous report, no significant association between XPD polymorphisms and melanoma risk was found in 176 melanoma cases and 177 controls (odds ratio (OR)=1.5, 95% confidence interval (CI)=0.9-2.5 for 312Asn; OR=1.3, 95% CI=0.8-2.1 for 751Gln, adjusted for age, gender, dysplastic naevi and pigmentation characteristics). However, XPD variants were associated with increased risk in older (>50 years) subjects (OR=3.4, 95% CI=1.6-7.3 for 312Asn; OR=2.3, 95% CI=1.1-4.9 for 751Gln). The 751Gln allele was associated with elevated melanoma risk among subjects without dysplastic naevi (OR=2.6, 95% CI=1.1-6.4). Subjects with low tanning ability and XPD variants exhibited a nonsignificant increase of melanoma risk (OR=2.3, 95% CI=0.7-7.0 for 312Asn; OR=3.0, 95% CI=1.0-8.8 for 751Gln). DNA repair capacity was slightly decreased in subjects carrying 751Gln alleles. XPD variants may modify melanoma risk in subjects with specific host characteristics, such as older age, lack of dysplastic naevi or low tanning ability.

Cutaneous malignant melanoma (CMM) is a malicious human skin cancer that primarily affects individuals with light pigmentation and heavy sun exposure, but also has a known familial association. Multiple genes and polymorphisms have been reported as low-penetrance susceptibility loci for CMM. Here, we examined 33 candidate polymorphisms located in 11 pigmentation genes and the vitamin D receptor gene (VDR) in a population of 130 cutaneous melanoma patients and 707 healthy controls. The genotypes obtained were evaluated for main association effects and potential gene-gene interactions. MC1R, TYR, VDR and SLC45A2 genes were found to be associated with CMM in our population. The results obtained for major function MC1R mutations were the most significant [with odds ratio (OR)=1.787, confidence interval (CI)=1.320-2.419 and P=1.715(-4)], followed by TYR (rs1393350) (with OR=1.569, CI=1.162-2.118, P=0.003), VDR (GCCC haplotype in rs2238136-rs4516035-rs7139166-rs11568820 block) (with OR=5.653, CI=1.794-17.811, P=0.003) and SLC45A2 (rs16891982) (with OR=0.238, CI=0.057-0.987, P=0.048). The study also detected significant intermolecular epistatic effects between MC1R and TYR, SLC45A2 and VDR, HERC2 and VDR, OCA2 and TPCN2, as well as intramolecular interactions between variants within the genes MC1R and VDR. In the final multivariate logistic regression model for CMM development, only the gene-gene interactions discovered remained significant, showing that epistasis may be an important factor in the risk of melanoma.

Background Given the increasing incidence in cutaneous malignant melanoma (CMM) and the recent changes in the treatment landscape, it is important to understand stage-specific overall and recurrence-free survival patterns in Europe. Despite publications such as EUROCARE-5, there is limited information on stage-specific survival for CMM in Europe. Method We carried out a systematic literature review to provide an up-to-date summary of stage-specific survival and recurrence-free survival patterns in patients with CMM in Europe. Studies were included if they were published in Medline during the past 12 years and included information on stage-specific survival and/or recurrence in CMM. Results Of the 8,749 studies identified, 26 studies were included, representing nine countries. Collectively, the studies covered a population of 152,422 patients and included data from 1978 to 2011. Randomized clinical trials and single-center observational studies comprised the most common study designs, including five large registry-based studies. Stage-specific information for survival and recurrence varied: 5-year overall survival: 95%–100% (stage I), 65%–92.8% (stage II), 41%–71% (stage III), and 9%–28% (stage IV); 5-year relapse-free survival was reported less frequently: 56% (stage II), and 28%–44% (stage III). Studies reporting survival by sentinel node (SN) status reported 5-year overall survival as 80%–95% for negative SN (stage I/II) and 35%–75% for positive SN (stage III) status; recurrence-free survival at 5 years: 76%–90% for negative and 35%–58% for positive SN status. Some studies included comparisons of survival by key patient sociodemographic characteristics, suggesting that these have a substantial influence on survival and recurrence estimates. Conclusion The studies identified in this review show large variations in stage-specific overall and recurrence-free survival by study type and by country. Owing to differing study designs and populations, it is difficult to make detailed comparisons. Large population-based studies that include stage-specific survival and recurrence in Europe are therefore important.

Solar ultraviolet (UV) radiation is the main source of vitamin D production and is also the most important environmental risk factor for cutaneous malignant melanoma (CMM) development. In the present study the relationships between daily or seasonal UV radiation doses and vitamin D status, dietary vitamin D intake and CMM incidence rates at different geographical latitudes were investigated. North-South gradients of 25-hydroxyvitamin D (25(OH)D) generation and CMM induction were calculated, based on known action spectra, and compared with measured vitamin D levels and incidence rates of CMM. The relative roles of UVA and UVB in CMM induction are discussed. Latitudinal dependencies of serum 25(OH)D levels and CMM incidence rates can only partly be explained by ambient UV doses. The UV sensitivity is different among populations with different skin color. This is well known for CMM, but seems also to be true for vitamin D status. The fact that UV-induced vitamin D may reduce the risk of CMM complicates the discussion. To some extent high dietary vitamin D intake seems to compensate low UV doses.

Introduction of targeted therapy in the treatment of metastatic cutaneous malignant melanoma (CMM) has improved clinical outcome during the last years. However, only in a subset of the CMM patients, this will lead to long-term effects. CEBPB is a transcription factor that has been implicated in various physiological and pathological processes, including cancer development. We have investigated its prognostic impact on CMM and unexpectedly found that higherCEBPBmRNA levels correlated with a longer overall survival. Furthermore, in a small cohort of patients with metastatic CMM treated with BRAF-inhibitors, higher levels ofCEBPBmRNA expression in the tumor cells prior treatment correlated to a longer progression-free survival. We have characterized an overlapping antisense transcript,CEBPB-AS1, with the aim to investigate the regulation of CEBPB expression in CMM and its impact on BRAF-inhibitor sensitivity. We demonstrated that silencing ofCEBPB-AS1resulted in epigenetic modifications in the CEBPB promoter and in increasedCEBPBmRNA and protein levels, inhibited proliferation and partially resensitized BRAF-inhibitor resistant CMM cells to this drug-induced apoptosis. Our data suggest that targetingCEBPB-AS1may represent a valuable tool to sensitize CMM cells to the BRAF-inhibitor-based therapies.