Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BACKGROUND: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited. METHODS: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates. RESULTS: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis. CONCLUSIONS: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10-8) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.

Cutaneous malignant melanoma and Parkinson disease: Common pathways?

The mechanisms underlying the high prevalence of cutaneous malignant melanoma (CMM) in Parkinson disease (PD) are unclear, but plausibly involve common pathways. 129Ser-phosphorylated α-synuclein, a pathological PD hallmark, is abundantly expressed in CMM, but not in normal skin. In inherited PD, PARK genes harbor germline mutations; the same genes are somatically mutated in CMM, or their encoded proteins are involved in melanomagenesis. Conversely, genes associated with CMM affect PD risk. PD/CMM-targeted cells share neural crest origin and melanogenesis capability. Pigmentation gene variants may underlie their susceptibility. We review putative genetic intersections that may be suggestive of shared pathways in neurodegeneration/melanomagenesis. Ann Neurol 2016;80:811-820.

Parkinson disease (PARK) genes are somatically mutated in cutaneous melanoma.

OBJECTIVE: To assess whether Parkinson disease (PD) genes are somatically mutated in cutaneous melanoma (CM) tissue, because CM occurs in patients with PD at higher rates than in the general population and PD is more common than expected in CM cohorts. METHODS: We cross-referenced somatic mutations in metastatic CM detected by whole-exome sequencing with the 15 known PD (PARK) genes. We computed the empirical distribution of the sum of mutations in each gene (Smut) and of the number of tissue samples in which a given gene was mutated at least once (SSampl) for each of the analyzable genes, determined the 90th and 95th percentiles of the empirical distributions of these sums, and verified the location of PARK genes in these distributions. Identical analyses were applied to adenocarcinoma of lung (ADENOCA-LUNG) and squamous cell carcinoma of lung (SQUAMCA-LUNG). We also analyzed the distribution of the number of mutated PARK genes in CM samples vs the 2 lung cancers. RESULTS: Somatic CM mutation analysis (n = 246) detected 315,914 mutations in 18,758 genes. Somatic CM mutations were found in 14 of 15 PARK genes. Forty-eight percent of CM samples carried ≥1 PARK mutation and 25% carried multiple PARK mutations. PARK8 mutations occurred above the 95th percentile of the empirical distribution for SMut and SSampl. Significantly more CM samples harbored multiple PARK gene mutations compared with SQUAMCA-LUNG (p = 0.0026) and with ADENOCA-LUNG (p < 0.0001). CONCLUSIONS: The overrepresentation of somatic PARK mutations in CM suggests shared dysregulated pathways for CM and PD.

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions.

At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the "missing heritability."

The melanocortin 1 receptor (Mc1r) variants do not account for the co-occurrence of Parkinson's disease and malignant melanoma.

Parkinson's disease (PD) is characterized by loss of melanin-positive dopaminergic neurons in the substantia nigra. Malignant melanoma (MM), a melanocyte-derived neoplasm, occurs with higher than expected frequency among PD patients. Red-haired individuals exhibit a threefold risk for developing MM than dark-haired people; PD risk also increases with lighter hair color. One plausible explanation for the associations between MM, hair color, and PD is the melanocortin-1 receptor (MC1R) gene that plays a key role in hair and skin pigmentation as well as in MM predisposition. We hypothesized that specific MC1R variants may predispose to both MM and PD. Genotyping of the MC1R gene was performed for 16 PD patients with MM (PD+ MM+) and for three sets of age, sex, and ethnically matched controls, including 36 patients with PD (PD+ MM-), 37 with MM (PD- MM+) and 37 with neither diagnosis (PD- MM-). No association was found between MC1R variants and the co-occurrence of PD and MM. The risk for MM was higher in carriers of two MC1R variants versus with no MC1R variant (odds ratio (OR)=5.0, 95% confidence interval (CI) 1.7-14.4, p=0.003). The risk for PD in carriers of two MC1R variants was markedly lower (OR=0.213, 95% CI 0.063-0.725) compared with individuals with no MC1R variant (p=0.013). In this study, MC1R variants were not associated with both MM and PD. Further studies in larger cohorts are necessary to confirm these preliminary results.

The effect on melanoma risk of genes previously associated with telomere length.

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.

A variant in FTO shows association with melanoma risk not due to BMI.

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.

Serum levels of 25-hydroxy-vitamin D3 among sun-protected outdoor workers in Israel.

The objective of this study was to evaluate the effect of reduced sun exposure of outdoor workers on vitamin D status using different modalities of sun protection, for primary prevention of skin cancer. 25-OH-D3 measurements were performed in two successive winters, 8 (interim) and 20 months after initiation of the study, in three groups of male outdoor workers, enrolled in either a complete, partial or minimal sun protection program. Ambient solar UVB radiation was monitored simultaneously. No intragroup or intergroup differences were observed between the interim- and postintervention measurements of mean 25-OH-D3, which were close to 30 ng mL(-1). Significant risk factors for postintervention 25-OH-D3 levels >33.8 ng mL(-1) (a surrogate for reduced sun protection) were: previous sunburn episodes (OR 2.5; 95% CI 1.01-6.3; P=0.05) and younger age (OR 0.92; 95 CI 0.86-0.98; P=0.009). Outdoor workers of Western, compared with those of Eastern paternal origin had a borderline significant risk (OR 2.4; 95% CI 0.9-6.3; P=0.07). A borderline significant effect (OR 2.9; 95% CI 0.97-10.1; P=0.085) was also noted for those in the minimal intervention group. In conclusion, sun protection among outdoor workers following a successful intervention did not suppress mean winter 25-OH-D3.

Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination.

OBJECTIVE: To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma. DESIGN: A cross-sectional, web-based survey. SETTING: Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL). PARTICIPANTS: A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%). MAIN OUTCOME MEASURES: Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE). RESULTS: After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE. CONCLUSIONS: Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources.

Perceptions of genetic research and testing among members of families with an increased risk of malignant melanoma.

BACKGROUND: Several melanoma susceptibility genes have been identified. As part of the international genetic research programme of the GenoMEL consortiums research on genetic mutations in melanoma families, the aim of this study was to examine family members' views about their risk of melanoma, gene testing and genetic research. METHODS: Self-report data were gathered using online and paper-based surveys available in four languages among 312 individuals (62% from Europe, 18% from Australia, 13% from the United States of America (USA) and 7% from Israel). RESULTS: Fifty three percent had been diagnosed with a melanoma, and 12% had a positive susceptibility gene test result. Respondents with many moles and freckles were more likely to perceive themselves at risk for developing melanoma (odds ratio [OR](Freckles)=2.24 with 95% confidence interval [CI]=1.18-4.26; OR(Many moles)=6.92, 95%CI=2.37-20.23). Respondents who had received a non-informative (negative) genetic test result were much less likely to perceive themselves at increased risk (OR=0.17, 95% CI=0.04-0.73). Safe-guards were perceived as important to protect genetic information, but there was also support for the storage and exchange of such information. Overall, respondents were in favour of genetic testing, even if current knowledge about melanoma risk genes is still limited. Contrary to previous studies, participants reported that a non-informative (negative) genetic test result, although not necessarily indicative of lower risk of melanoma, would be likely to reduce their practise of preventive behaviours. CONCLUSIONS: Participants were influenced by their phenotype and test results in risk estimations. They expressed positive views on genetic research and towards genetic testing, but reported that a non-informative (negative) test result might be associated with an (erroneous) perception of reduced risk and fewer preventive behaviours. These results highlight the urgency of improving the quality of genetic counselling and increasing the effectiveness of communication regarding genetic test results.

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3.

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.

Genome-wide association study identifies three new melanoma susceptibility loci.

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.

Predictors of sun protection behaviors and severe sunburn in an international online study.

BACKGROUND: The incidence of melanoma continues to increase in many countries, and primary prevention of melanoma includes avoidance of sunburn as well as adequate sun protection behavior. The aim of this study was to examine the prevalence of self-reported sun protection behaviors and sunburn in users of the Internet, and to identify the demographic, clinical, and attitudinal/motivational correlates of sun protection behaviors. METHODS: Self-report data were gathered on behalf of the GenoMEL consortium using an online survey available in 10 different languages, and 8,178 individuals successfully completed at least 80% of survey items, with 73% of respondents from Europe, 12% from Australia, 7% from the United States, 2% from Israel, and 6% from other countries. RESULTS: Half of all respondents and 27% of those with a previous melanoma reported at least one severe sunburn during the previous 12 months. The strongest factors associated with sun protection behavior were perceived barriers to protection (beta = -0.44/beta = -0.37), and respondents who reported a positive attitude toward suntans were less likely to protect (beta = -0.16/beta = -0.14). Reported use of protective clothing and shade, as well as avoidance of midday sun exposure, were more strongly related to reduced risk of sunburn than sunscreen use. CONCLUSIONS: Despite widespread dissemination of public health messages about the importance of sun protection, a substantial proportion of this international sample, including respondents with a previous melanoma, reported inadequate sun protection behaviors resulting in severe sunburn. IMPACT: Future strategies to decrease sunburn should target the practical, social, and psychological barriers associated with nonuptake of sun protection.

Melanoma risk factors, perceived threat and intentional tanning: an international online survey.

Cutaneous melanoma continues to increase in incidence in many countries, and intentional tanning is a risk factor for melanoma. The aim of this study was to understand how melanoma risk factors, perceived threat and preferences for a suntan relate to intentional tanning. Self-report data were collected on behalf of GenoMEL (www.genomel.org) from the general population using an online survey. A total of 8178 individuals completed the survey, with 72.8% of respondents being from Europe, 12.1% from Australia, 7.1% from the US, 2.5% from Israel and 5.5% from other countries. Seven percent of respondents had previously been diagnosed with melanoma and 8% had at least one first-degree relative with a previous melanoma. Overall, 70% reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. The total number of risk factors was positively correlated with perceived risk of melanoma [correlation coefficient (rho) = 0.27], and negatively correlated with intentional tanning (rho = -0.16). Preference for a dark suntan was the strongest predictor of intentional tanning [regression coefficient (beta) = 0.35, P<0.001], even in those with a previous melanoma (beta = 0.33, P<0.01). A substantial proportion of participants reported having phenotypic and behavioural risk factors for melanoma. The preference regarding suntans seemed more important in the participants' decision to intentionally tan than their perceived risk of developing melanoma, and this finding was consistent among respondents from different countries. The drive to sunbathe to tan is a key factor to be moderated if melanoma incidence is to be reduced.

Genome-wide association study identifies three loci associated with melanoma risk.

We report a genome-wide association study of melanoma conducted by the GenoMEL consortium based on 317K tagging SNPs for 1,650 selected cases and 4,336 controls, with replication in an additional two cohorts (1,149 selected cases and 964 controls from GenoMEL, and a population-based case-control study in Leeds of 1,163 cases and 903 controls). The genome-wide screen identified five loci with genotyped or imputed SNPs reaching P < 5 x 10(-7). Three of these loci were replicated: 16q24 encompassing MC1R (combined P = 2.54 x 10(-27) for rs258322), 11q14-q21 encompassing TYR (P = 2.41 x 10(-14) for rs1393350) and 9p21 adjacent to MTAP and flanking CDKN2A (P = 4.03 x 10(-7) for rs7023329). MC1R and TYR are associated with pigmentation, freckling and cutaneous sun sensitivity, well-recognized melanoma risk factors. Common variants within the 9p21 locus have not previously been associated with melanoma. Despite wide variation in allele frequency, these genetic variants show notable homogeneity of effect across populations of European ancestry living at different latitudes and show independent association to disease risk.