Signal pathways of melanoma and targeted therapy

Melanoma is the most lethal skin cancer that originates from the malignant transformation of melanocytes. Although melanoma has long been regarded as a cancerous malignancy with few therapeutic options, increased biological understanding and unprecedented innovations in therapies targeting mutated driver genes and immune checkpoints have substantially improved the prognosis of patients. However, the low response rate and inevitable occurrence of resistance to currently available targeted therapies have posed the obstacle in the path of melanoma management to obtain further amelioration. Therefore, it is necessary to understand the mechanisms underlying melanoma pathogenesis more comprehensively, which might lead to more substantial progress in therapeutic approaches and expand clinical options for melanoma therapy. In this review, we firstly make a brief introduction to melanoma epidemiology, clinical subtypes, risk factors, and current therapies. Then, the signal pathways orchestrating melanoma pathogenesis, including genetic mutations, key transcriptional regulators, epigenetic dysregulations, metabolic reprogramming, crucial metastasis-related signals, tumor-promoting inflammatory pathways, and pro-angiogenic factors, have been systemically reviewed and discussed. Subsequently, we outline current progresses in therapies targeting mutated driver genes and immune checkpoints, as well as the mechanisms underlying the treatment resistance. Finally, the prospects and challenges in the development of melanoma therapy, especially immunotherapy and related ongoing clinical trials, are summarized and discussed.

Epidemiology and Risk Factors of Melanoma: A Review

We are currently witnessing a worldwide increase in the incidence of melanoma. Incidence in Europe is about 25 cases per 100,000 population, while in Australia it reaches a rate of 60 new cases per 100,000. While the epidemiological curves of the 1980's and 1990's suggested an increase in the incidence of melanoma across all age groups, the last 10 years’ data indicates a 5% reduction in the incidence of thin melanoma in young individuals aged between 15 and 24. This suggests a positive impact of primary prevention campaigns [1-2]. The risk factors associated with melanoma are different and multifactorial: on one hand, there is a genetic predisposition, as evidenced by the increased risk in patients with dysplastic nevus syndrome, with familial melanoma or familial melanoma syndromes; on the other hand, the unprotected interaction between UV rays and phototypes I-II increases the risk of developing melanoma, especially in case of sunburns in pediatric age. This review aims to summarize melanoma epidemiology and risk factors.

Melanoma Epidemiology and Early Detection in Europe: Diversity and Disparities

Melanoma claims annually more than 20,000 lives in Europe and is an important public health burden through its continuously increasing incidence and with its high mortality, costs, and complexity of care in advanced stages. Epidemiological surveillance is indispensable for the research into its causes, new prognostic markers, and innovative therapies, as well as for the building of efficient cancer control plans. However, important differences in the sources and availability of accurate epidemiological data exist among European countries and regions, contributing to a heterogeneous picture with 20-fold differences in the reported national melanoma incidence rates, divergent mortality trends, and solid disparities in survival across the Continent. Countries in the eastern half of Europe report the lowest incidence rates, but high case fatality, persisting and increasing mortality, a higher proportion of thicker tumors and late diagnosis, and lower survival rates. They are the least well equipped with quality cancer registration and reporting, and they lag behind in efficient cancer control plans implementation. This review highlights the main differences in melanoma epidemiology across Europe, together with an insight into their underlying causes in the areas of melanoma registration, early diagnosis, and prevention. These differences should be acknowledged and understood by physicians, researchers, and all stakeholders involved in improving melanoma care and outcomes, as no one-size-fits-all solution can tackle the melanoma problem in Europe. Instead, there is a need for nuanced strategies, adapted to the heterogeneous national and regional contexts, that would build on European diversity to eliminate the outcome disparities.