Global burden of cutaneous melanoma attributable to ultraviolet radiation in 2012 : Global burden of melanoma attributable to UVR

Melanin pigmentation protects the skin from the damaging effects of ultraviolet radiation (UVR). There are two types of melanin, the red phaeomelanin and the black eumelanin, both of which are present in human skin. Eumelanin is photoprotective whereas phaeomelanin, because of its potential to generate free radicals in response to UVR, may contribute to UV-induced skin damage. Individuals with red hair have a predominance of phaeomelain in hair and skin and/or a reduced ability to produce eumelanin, which may explain why they fail to tan and are at risk from UVR. In mammals the relative proportions of phaeomelanin and eumelanin are regulated by melanocyte stimulating hormone (MSH), which acts via its receptor (MC1R), on melanocytes, to increase the synthesis of eumelanin and the product of the agouti locus which antagonises this action. In mice, mutations at either the MC1R gene or agouti affect the pattern of melanogenesis resulting in changes in coat colour. We now report the presence of MC1R gene sequence variants in humans. These were found in over 80% of individuals with red hair and/or fair skin that tans poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response. Our findings suggest that in humans, as in other mammals, the MC1R is a control point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response.

In the past decade, major advances have been made in the understanding of melanoma. New predisposition genes have been reported and key somatic events, such as BRAF mutation, directly translated into therapeutic management. Surgery for localised melanoma and regional lymph node metastases is the standard of care. Sentinel-node biopsy provides precise staging, but has not been reported to affect survival. The effect of lymph-node dissection on survival is a topic of investigation. Two distinct approaches have emerged to try to extend survival in patients with metastatic melanoma: immunomodulation with anti-CTLA4 monoclonal antibodies, and targeted therapy with BRAF inhibitors or MEK inhibitors for BRAF-mutated melanoma. The combination of BRAF inhibitors and MEK inhibitors might improve progression-free survival further and, possibly, increase overall survival. Response patterns differ substantially-anti-CTLA4 immunotherapy can induce long-term responses, but only in a few patients, whereas targeted drugs induce responses in most patients, but nearly all of them relapse because of pre-existing or acquired resistance. Thus, the long-term prognosis of metastatic melanoma remains poor. Anti-PD1 and anti-PDL1 antibodies have emerged as breakthrough drugs for melanoma that have high response rates and long durability. Biomarkers that have predictive value remain elusive in melanoma, although emerging data for adjuvant therapy indicate that interferon sensitivity is associated with ulceration of the primary melanoma. Intense investigation continues for clinical and biological markers that predict clinical benefit of immunotherapeutic drugs, such as interferon alfa or anti-CTLA4 antibodies, and the mechanisms that lead to resistance of targeted drugs. Copyright © 2014 Elsevier Ltd. All rights reserved.

The incidence of cutaneous malignant melanoma has steadily increased over the past 50 years in predominately fair-skinned populations. This increase is reported to have leveled off recently in several Northern and Western European countries, Australia, New Zealand and in North America. We studied the global patterns and time trends in incidence of melanoma by country and sex, with a focus on and age- and cohort-specific variations. We analyzed the incidence data from 39 population-based cancer registries, examining all-ages and age-truncated standardized incidence rates of melanoma, estimating the annual percentage change and incidence rate ratios from age-period-cohort models. Incidence rates of melanoma continue to rise in most European countries (primarily Southern and Eastern Europe), whereas in Australia, New Zealand, the U.S., Canada, Israel and Norway, rates have become rather stable in recent years. Indications of a stabilization or decreasing trend were observed mainly in the youngest age group (25-44 years). Rates have been rising steadily in generations born up to the end of the 1940s, followed by a stabilization or decline in rates for more recently born cohorts in Australia, New Zealand, the U.S., Canada and Norway. In addition to the birth cohort effect, there was a suggestion of a period-related influence on melanoma trends in certain populations. Although our findings provide support that primary and secondary prevention can halt and reverse the observed increasing burden of melanoma, they also indicate that those prevention measures require further endorsement in many countries. Copyright © 2012 UICC.