What is New in Melanoma Genetics and Treatment?

New therapies for advanced melanoma have led to major advances, which, for the first time, showed improved survival for patients with this very challenging neoplasm. These new treatments are based on gene-targeted therapies or stimulation of immune responses. However, these treatments are not without challenges in terms of resistance and toxicity. Physicians should be aware of these side effects as prompt treatment may save lives. Melanoma genetics is also unravelling new genetic risk factors involving telomere genes as well as new gene pathways at the somatic level which may soon become therapeutic targets. It is also shedding new light onto the pathology of this tumour with links to neural diseases and longevity

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P\u3c5 × 10−8), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk

A multicentre epidemiological study on sunbed use and cutaneous melanoma in Europe

A large European case-control study investigated the association between sunbed use and cutaneous melanoma in an adult population aged between 18 and 49 years. Between 1999 and 2001 sun and sunbed exposure was recorded in 597 newly diagnosed melanoma cases and 622 controls in Belgium, France, The Netherlands, Sweden and the UK. Fifty three precent of cases and 57% of controls ever used sunbeds. The overall adjusted odds ratio (OR) associated with ever sunbed use was 0.90 (95% CI: 0.71-1.14). There was a South-to-North gradient with high prevalence of sunbed exposure in Northern Europe and lower prevalence in the South (prevalence of use in France 20%, OR: 1.19 (0.68-2.07) compared to Sweden, prevalence 83%, relative risk 0.62 (0.26-1.46)). Dose and lag-time between first exposure to sunbeds and time of study were not associated with melanoma risk, neither were sunbathing and sunburns (adjusted OR for mean number of weeks spent in sunny climates >14 years: 1.12 (0.88-1.43); adjusted OR for any sunburn >14 years: 1.16 (0.9-1.45)). Host factors such as numbers of naevi and skin type were the strongest risk indicators for melanoma. Public health campaigns have improved knowledge regarding risk of UV-radiation for skin cancers and this may have led to recall and selection biases in both cases and controls in this study. Sunbed exposure has become increasingly prevalent over the last 20 years, especially in Northern Europe but the full impact of this exposure on skin cancers may not become apparent for many years

Sunny holidays before and after melanoma diagnosis are respectively associated with lower breslow thickness and lower relapse rates in Italy

Background: Previous studies have reported an association between sun exposure and improved cutaneous melanoma (CM) survival. We analysed the association of UV exposure with prognostic factors and outcome in a large melanoma cohort. Methods: A questionnaire was given to 289 (42%) CM patients at diagnosis (Group 1) and to 402 CM patients (58%) during follow-up (Group 2). Analyses were carried out to investigate the associations between sun exposure and melanoma prognostic factors and survival. Results: Holidays in the sun two years before CM diagnosis were significantly associated with lower Breslow thickness (p=0.003), after multiple adjustment. Number of weeks of sunny holidays was also significantly and inversely associated with thickness in a dose-dependent manner (p=0.007). However when stratifying by gender this association was found only among women (p=0.0004) the risk of CM recurrence in both sexes was significantly lower in patients (n=271) who had holidays in the sun after diagnosis, after multiple adjustment including education: HR=0.30 (95%CI:0.10-0.87; p=0.03) conclusions: Holidays in the sun were associated with thinner melanomas in women and reduced rates of relapse in both sexes. However, these results do not prove a direct causal effect of sun exposure on survival since other confounding factors, such as vitamin D serum levels and socio-economic status, may play a role. Other factors in sun seeking individuals may also possibly affect these results

Genome-Wide Association Reveals Pigmentation Genes Play a Role in Skin Aging

Loss of fine skin patterning is a sign of both aging and photoaging. Studies investigating the genetic contribution to skin patterning offer an opportunity to better understand a trait that influences both physical appearance and risk of keratinocyte skin cancer. We undertook a meta-analysis of genome-wide association studies (GWAS) of a measure of skin pattern (microtopography score) damage in 1,671 twin pairs and 1,745 singletons (N = 5,087) drawn from three independent cohorts. We identified that rs185146 near SLC45A2 is associated with a skin aging trait (p = 4.1 × 10-9); to our knowledge this is previously unreported. We also confirm previously identified loci, rs12203592 near IRF4 (p = 8.8 × 10-13), and rs4268748 near MC1R (p = 1.2 × 10-15). At all three loci we highlight putative functionally relevant SNPs. There are a number of red hair/low pigmentation alleles of MC1R; we found that together these MC1R alleles explained 4.1% of variance in skin pattern damage. We also show that skin aging and reported experience of sunburns was proportional to the degree of penetrance for red hair of alleles of MC1R. Our work has uncovered genetic contributions to skin aging and confirmed previous findings, showing that pigmentation is a critical determinate of skin aging

Genome-wide meta-analysis implicates mediators of hair follicle development and morphogenesis in risk for severe acne

Acne vulgaris is a highly heritable common, chronic inflammatory disease of the skin for which five genetic risk loci have so far been identified. Here, we perform a genome-wide association study of 3823 cases and 16,144 controls followed by meta-analysis with summary statistics from a previous study, with a total sample size of 26,722. We identify 20 independent association signals at 15 risk loci, 12 of which have not been previously implicated in the disease. Likely causal variants disrupt the coding region of WNT10A and a P63 transcription factor binding site in SEMA4B. Risk alleles at the 1q25 locus are associated with increased expression of LAMC2, in which biallelic loss-of-function mutations cause the blistering skin disease epidermolysis bullosa. These findings indicate that variation affecting the structure and maintenance of the skin, in particular the pilosebaceous unit, is a critical aspect of the genetic predisposition to severe acne

Genetics of skin color variation in Europeans: genome-wide association studies with functional follow-up

In the International Visible Trait Genetics (VisiGen) Consortium, we investigated the genetics of human skin color by combining a series of genome-wide association studies (GWAS) in a total of 17,262 Europeans with functional follow-up of discovered loci. Our GWAS provide the first genome-wide significant evidence for chromosome 20q11.22 harboring the ASIP gene being explicitly associated with skin color in Europeans. In addition, genomic loci at 5p13.2 (SLC45A2), 6p25.3 (IRF4), 15q13.1 (HERC2/OCA2), and 16q24.3 (MC1R) were confirmed to be involved in skin coloration in Europeans. In follow-up gene expression and regulation studies of 22 genes in 20q11.22, we highlighted two novel genes EIF2S2 and GSS, serving as competing functional candidates in this region and providing future research lines. A genetically inferred skin color score obtained from the 9 top-associated SNPs from 9 genes in 940 worldwide samples (HGDP-CEPH) showed a clear gradual pattern in Western Eurasians similar to the distribution of physical skin color, suggesting the used 9 SNPs as suitable markers for DNA prediction of skin color in Europeans and neighboring populations, relevant in future forensic and anthropological investigations

Pigmentation and Vitamin D Metabolism in Caucasians: Low Vitamin D Serum Levels in Fair Skin Types in the UK

Background: Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated. Methodology/Principal Findings: We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p,0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p,0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001). Conclusions/Significance: Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in vie