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1.  A variant in FTO shows association with melanoma risk not due to BMI 
Iles, Mark M | Law, Matthew H | Stacey, Simon N | Han, Jiali | Fang, Shenying | Pfeiffer, Ruth | Harland, Mark | MacGregor, Stuart | Taylor, John C | Aben, Katja K | Akslen, Lars A | Avril, Marie-Françoise | Azizi, Esther | Bakker, Bert | Benediktsdottir, Kristrun R | Bergman, Wilma | Scarrà, Giovanna Bianchi | Brown, Kevin M | Calista, Donato | Chaudru, Valerié | Fargnoli, Maria Concetta | Cust, Anne E | Demenais, Florence | de Waal, Anne C | Dębniak, Tadeusz | Elder, David E | Friedman, Eitan | Galan, Pilar | Ghiorzo, Paola | Gillanders, Elizabeth M | Goldstein, Alisa M | Gruis, Nelleke A | Hansson, Johan | Helsing, Per | Hočevar, Marko | Höiom, Veronica | Hopper, John L | Ingvar, Christian | Janssen, Marjolein | Jenkins, Mark A | Kanetsky, Peter A | Kiemeney, Lambertus A | Lang, Julie | Lathrop, G Mark | Leachman, Sancy | Lee, Jeffrey E | Lubiński, Jan | Mackie, Rona M | Mann, Graham J | Mayordomo, Jose I | Molven, Anders | Mulder, Suzanne | Nagore, Eduardo | Novaković, Srdjan | Okamoto, Ichiro | Olafsson, Jon H | Olsson, Håkan | Pehamberger, Hubert | Peris, Ketty | Grasa, Maria Pilar | Planelles, Dolores | Puig, Susana | Puig-Butille, Joan Anton | Randerson-Moor, Juliette | Requena, Celia | Rivoltini, Licia | Rodolfo, Monica | Santinami, Mario | Sigurgeirsson, Bardur | Snowden, Helen | Song, Fengju | Sulem, Patrick | Thorisdottir, Kristin | Tuominen, Rainer | Van Belle, Patricia | van der Stoep, Nienke | van Rossum, Michelle M | Wei, Qingyi | Wendt, Judith | Zelenika, Diana | Zhang, Mingfeng | Landi, Maria Teresa | Thorleifsson, Gudmar | Bishop, D Timothy | Amos, Christopher I | Hayward, Nicholas K | Stefansson, Kari | Bishop, Julia A Newton | Barrett, Jennifer H
Nature genetics  2013;45(4):428-432.
We report the results of an association study of melanoma 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 a novel association between several single nucleotide polymorphisms (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 OR for A=1.16). As well as identifying a novel melanoma susceptibility locus, this is 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 show 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.
doi:10.1038/ng.2571
PMCID: PMC3640814  PMID: 23455637
2.  Predictors of Sun Protection Behaviours and Severe Sunburn inan International on-line 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 behaviour. The aim of this study was to examine the prevalence of self-reported sun protection behaviours and sunburn in users of the Internet, and to identify the demographic, clinical and attitudinal/motivational correlates of sun protection behaviours.
Methods
Self-report data were gathered on behalf of GenoMEL (www.genomel.org) 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 USA, 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 behaviour were perceived barriers to protection (β=−0.44/β=−0.37), and respondents who reported a positive attitude towards suntans were less likely to protect (β=−0.16/β=−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 behaviours resulting in severe sunburn.
Impact
Future strategies to decrease sunburn should target the practical, social and psychological barriers associated with non-uptake of sun protection.
doi:10.1158/1055-9965.EPI-10-0196
PMCID: PMC3672402  PMID: 20643826
Sun exposure; Sunburn; Sun protection; Melanoma
3.  Melanoma Risk Factors, Perceived threat and Intentional Tanning: An Online Survey 
Background
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.
Methods
Self-report data were collected on behalf of GenoMEL (www.genomel.org) from members of the general population using an online survey. A total of 8,178 individuals successfully completed at least 80% of the survey, with 72.8% of respondents from Europe, 12.1% from Australia, 7.1% from the USA, 2.5% from Israel, and 5.5% from other countries.
Results
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% of the respondents reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. Total number of objective risk factors was positively correlated with perceived risk of melanoma (correlation coefficient (ρ)=0.27), and negatively correlated with intentional tanning (ρ=−0.16). Preference for a dark suntan was the strongest predictor of intentional tanning (regression coefficient (β)=0.35, p<0.001), even in those with a previous melanoma (β=0.33, p<0.01).
Conclusions
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 in order to tan appears to be a key psychological factor to be moderated if melanoma incidence is to be reduced.
doi:10.1097/CEJ.0b013e3283354847
PMCID: PMC3672405  PMID: 20093934
Intentional tanning; Sunbathing, Suntan; Perceived threat; Melanoma; Risk factors; Familial risk
4.  Genome-Wide Analysis of Gene and Protein Expression of Dysplastic Naevus Cells 
Journal of Skin Cancer  2012;2012:981308.
Cutaneous melanoma, a type of skin tumor originating from melanocytes, often develops from premalignant naevoid lesions via a gradual transformation process driven by an accumulation of (epi)genetic lesions. These dysplastic naevi display altered morphology and often proliferation of melanocytes. Additionally, melanocytes in dysplastic naevi show structural mitochondrial and melanosomal alterations and have elevated reactive oxygen species (ROS) levels. For this study we performed genome-wide expression and proteomic analysis of melanocytes from dysplastic naevus (DNMC) and adjacent normal skin (MC) from 18 patients. Whole genome expression profiles of the DNMC and MC of each individual patient subjected to GO-based comparative statistical analysis yielded significantly differentially expressed GO classes including “organellar ribosome,” “mitochondrial ribosome,” “hydrogen ion transporter activity,” and “prefoldin complex.” Validation of 5 genes from these top GO classes revealed a heterogeneous differential expression pattern. Proteomic analysis demonstrated differentially expressed proteins in DNMC that are involved in cellular metabolism, detoxification, and cytoskeletal organization processes, such as GTP-binding Rho-like protein CDC42, glutathione-S-transferase omega-1 and prolyl 4-hydroxylase. Collectively these results point to deregulation of cellular processes, such as metabolism and protein synthesis, consistent with the observed elevated oxidative stress levels in DNMC potentially resulting in oxidative DNA damage in these cells.
doi:10.1155/2012/981308
PMCID: PMC3515917  PMID: 23251804
5.  Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project: study design and methods for pooling results of genetic epidemiological studies 
Background
For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia.
Design and methods
Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling.
Discussion
Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields.
doi:10.1186/1471-2288-12-116
PMCID: PMC3502117  PMID: 22862891
Genetic epidemiology; Melanoma; Meta-analysis; Pooled-analysis; Skin cancer; Study design
6.  Effectiveness and causes for failure of surveillance of CDKN2A mutated melanoma families 
Background
For over 25 years families with an increased susceptibility to melanoma have been under surveillance at our institution.
Objective
To investigate the effectiveness of surveillance for CDKN2A mutated families and causes for failure of the program in patients with late detected tumours.
Methods
In a retrospective case-control study, Breslow thickness of melanomas diagnosed in relatives enrolled in the surveillance program were compared to melanomas of unscreened index patients. We investigated the influence of mode of detection and length of surveillance interval on outcome.
Results
Surveillance melanomas (n = 226, median thickness: 0.50 mm) had a significantly lower Breslow thickness (multiplication factor: 0.61 (95% CI 0.47 – 0.80), p < 0.001) than index melanomas (n = 40, median thickness: 0.98 mm). Index melanomas were more likely diagnosed with a Breslow thickness > 1.0 mm (Odds ratio: 3.1 (95% CI 1.2 – 8.1), p = 0.022). 53% of surveillance melanomas were diagnosed during regular screens, 7% during patients’ first screen, 20% in between regular screens, and 20% in patients who were non-compliant with the surveillance schedule.
The majority of surveillance melanomas (58%) were detected within 6 months after the last screen. There was no correlation between tumour thickness and the length of the screening interval for tumours diagnosed within 24 months since the last screen.
Limitations
The study is retrospective.
Conclusions
Surveillance was associated with earlier detection of melanomas. Noncompliance was an important cause for failing surveillance. Shortening surveillance intervals may advance detection of tumours, but may paradoxically not improve prognosis
doi:10.1016/j.jaad.2010.06.067
PMCID: PMC3138884  PMID: 21570154
Melanoma; Prevention & Control; Dysplastic nevus syndrome; Genes, CDKN2A
8.  A Novel Flexible Multiplex Bead-based Assay for Detecting Germline CDKN2A and CDK4 Variants in Melanoma-Prone Kindreds 
Background
The presence of recurrent high-risk mutations in CDKN2A and CDK4 among melanoma-prone kindreds suggests that a high-throughput, multiplex assay could serve as an effective initial screening tool. Moreover, with the emergence of new melanoma risk single nucleotide polymorphisms (SNPs) through genome-wide association studies, a flexible platform that can easily accommodate these new risk alleles is needed for more accurate genetic risk profiling. To this end, we have developed a novel melanoma-associated mutation detection method using a multiplex bead-based assay. This assay is suitable for high-throughput CDKN2A and CDK4 genotyping and can be eventually adapted to multiple loci across various constituent populations.
Methods
Genomic DNA from a 1603 subjects (1005 in training set, 598 in validation set) were amplified by multiplex PCR using five primer sets followed by multiplex allele-specific primer extension for 39 different known germline variants. The products were then sorted on an xMAP™ (formerly Tag-It™) array and detected by use of the Luminex xMAP™ system. Genotypes were compared to previously-determined sequence data.
Results
In the Toronto training cohort, variants were detected in 145 samples, giving complete concordance between the bead assay and direct sequencing results. Analysis of the 598 samples from the GenoMEL validation set led to identification of 150/155 expected variants (96.77% concordance). Overall, the bead assay correctly genotyped 1540/1603 (96.07%) of all individuals in the study and 1540/1545 (99.68%) of individuals whose mutations were represented in the probe set. Out of a total of 62,512 SNP calls, 62,517 (99.99%) were correctly assigned.
Conclusions
In this initial evaluation, the multiplex bead-based assay for familial melanoma appears to be a highly accurate method for genotyping CDKN2A and CDK4 variants.
doi:10.1038/jid.2010.331
PMCID: PMC3045700  PMID: 21085193
Melanoma; CDKN2A; CDK4; p14ARF; familial; high-throughput
9.  Management of Melanoma Families  
Cancers  2010;2(2):549-566.
In this review we have aimed to focus on the clinical management of familial melanoma patients and their relatives. Along this line three major topics will be discussed: (1) management/screening of familial melanoma families: what is advised and what is the evidence thereof; (2) variability of families worldwide with regard to clinical phenotype, including cancer spectrum and likelihood of finding germline mutations and (3) background information for clinicians on the molecular biology of familial melanoma and recent developments in this field.
doi:10.3390/cancers2020549
PMCID: PMC3835091  PMID: 24281082
: familial melanoma; hereditary melanoma; FAMMM syndrome; pancreatic carcinoma; management; surveillance; screening; DNA testing; CDKN2A
10.  Features associated with germline CDKN2A mutations: a GenoMEL study of melanoma‐prone families from three continents 
Journal of Medical Genetics  2006;44(2):99-106.
Background
The major factors individually reported to be associated with an increased frequency of CDKN2A mutations are increased number of patients with melanoma in a family, early age at melanoma diagnosis, and family members with multiple primary melanomas (MPM) or pancreatic cancer.
Methods
These four features were examined in 385 families with ⩾3 patients with melanoma pooled by 17 GenoMEL groups, and these attributes were compared across continents.
Results
Overall, 39% of families had CDKN2A mutations ranging from 20% (32/162) in Australia to 45% (29/65) in North America to 57% (89/157) in Europe. All four features in each group, except pancreatic cancer in Australia (p = 0.38), individually showed significant associations with CDKN2A mutations, but the effects varied widely across continents. Multivariate examination also showed different predictors of mutation risk across continents. In Australian families, ⩾2 patients with MPM, median age at melanoma diagnosis ⩽40 years and ⩾6 patients with melanoma in a family jointly predicted the mutation risk. In European families, all four factors concurrently predicted the risk, but with less stringent criteria than in Australia. In North American families, only ⩾1 patient with MPM and age at diagnosis ⩽40 years simultaneously predicted the mutation risk.
Conclusions
The variation in CDKN2A mutations for the four features across continents is consistent with the lower melanoma incidence rates in Europe and higher rates of sporadic melanoma in Australia. The lack of a pancreatic cancer–CDKN2A mutation relationship in Australia probably reflects the divergent spectrum of mutations in families from Australia versus those from North America and Europe. GenoMEL is exploring candidate host, genetic and/or environmental risk factors to better understand the variation observed.
doi:10.1136/jmg.2006.043802
PMCID: PMC2598064  PMID: 16905682
melanoma;  CDKN2A ; multiple primary melanomas; pancreatic cancer
11.  A Pooled Analysis of Melanocytic Naevus Phenotype and the Risk of Cutaneous Melanoma at Different Latitudes 
An abnormal naevus phenotype is associated with an increased risk of melanoma. We report a pooled analysis conducted using individual naevus data from 15 case-control studies (5,421 melanoma cases and 6,966 controls). The aims were to quantify better the risk, and to determine whether relative risk varied by latitude. Bayesian unconditional logistic random coefficients models were employed to study the risk associated with naevus characteristics. Participants with whole body naevus counts in the highest of four population-based categories had a greatly increased risk of melanoma compared with those in the lowest category (pooled odds ratio (pOR) 6.9 (95% confidence interval (CI): 4.4, 11.2) for those aged <50 years and pOR 5.1 (95% CI: 3.6, 7.5) for those aged ≥50). The pOR for presence compared with absence of any clinically atypical naevi was 4.0 (95% CI: 2.8, 5.8). The pORs for 1–2 and ≥3 large naevi on the body compared with none were 2.9 (95% CI: 1.9, 4.3) and 7.1 (95% CI: 4.7, 11.6), respectively. The relative heterogeneities among studies were small for most measures of naevus phenotype, except for the analysis of naevus counts on the arms, which may have been due to methodological differences among studies. The pooled analysis also suggested that an abnormal naevus phenotype is associated most with melanomas on intermittently sun-exposed sites. The presence of increased numbers of naevi, large naevi and clinically atypical naevi on the body are robust risk factors for melanoma showing little variation in relative risk among studies performed at different latitudes.
doi:10.1002/ijc.23869
PMCID: PMC2656967  PMID: 18792098
melanoma; naevus; latitude; pooled analysis; Bayesian
12.  Common sequence variants on 20q11.22 confer melanoma susceptibility 
Nature genetics  2008;40(7):838-840.
We conducted a genome-wide association pooling study for cutaneous melanoma and performed validation in samples totalling 2019 cases and 2105 controls. Using pooling we identified a novel melanoma risk locus on chromosome 20 (rs910873, rs1885120), with replication in two further samples (combined P <1 × 10-15). The odds ratio is 1.75 (1.53, 2.01), with evidence for stronger association in early onset cases.
doi:10.1038/ng.163
PMCID: PMC2755512  PMID: 18488026
13.  A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL) 
CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by “blind” exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.
doi:10.1016/j.ejca.2008.03.005
PMCID: PMC2494985  PMID: 18394881
CDKN2A; melanoma; mutation detection; sequencing; polymorphism; audit; DHPLC; False negative
14.  Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls 
Background Melanoma risk is related to sun exposure; we have investigated risk variation by tumour site and latitude.
Methods We performed a pooled analysis of 15 case–control studies (5700 melanoma cases and 7216 controls), correlating patterns of sun exposure, sunburn and solar keratoses (three studies) with melanoma risk. Pooled odds ratios (pORs) and 95% Bayesian confidence intervals (CIs) were estimated using Bayesian unconditional polytomous logistic random-coefficients models.
Results Recreational sun exposure was a risk factor for melanoma on the trunk (pOR = 1.7; 95% CI: 1.4–2.2) and limbs (pOR = 1.4; 95% CI: 1.1–1.7), but not head and neck (pOR = 1.1; 95% CI: 0.8–1.4), across latitudes. Occupational sun exposure was associated with risk of melanoma on the head and neck at low latitudes (pOR = 1.7; 95% CI: 1.0–3.0). Total sun exposure was associated with increased risk of melanoma on the limbs at low latitudes (pOR = 1.5; 95% CI: 1.0–2.2), but not at other body sites or other latitudes. The pORs for sunburn in childhood were 1.5 (95% CI: 1.3–1.7), 1.5 (95% CI: 1.3–1.7) and 1.4 (95% CI: 1.1–1.7) for melanoma on the trunk, limbs, and head and neck, respectively, showing little variation across latitudes. The presence of head and neck solar keratoses was associated with increased risk of melanoma on the head and neck (pOR = 4.0; 95% CI: 1.7–9.1) and limbs (pOR = 4.0; 95% CI: 1.9–8.4).
Conclusion Melanoma risk at different body sites is associated with different amounts and patterns of sun exposure. Recreational sun exposure and sunburn are strong predictors of melanoma at all latitudes, whereas measures of occupational and total sun exposure appear to predict melanoma predominately at low latitudes.
doi:10.1093/ije/dyp166
PMCID: PMC2689397  PMID: 19359257
Melanoma; recreational sun exposure; occupational sun exposure; total sun exposure; sunburn; solar keratoses
15.  Inherited variants in the MC1R gene and survival from cutaneous melanoma: a BioGenoMEL study 
Pigment Cell & Melanoma Research  2012;25(3):384-394.
Summary
Inherited MC1R variants modulate MITF transcription factor signaling, which in turn affects tumor cell proliferation, apoptosis, and DNA repair. The aim of this BioGenoMEL collaborative study in 10 melanoma cohorts was to test the hypothesis that inherited variants thereby moderate survival expectation. A survival analysis in the largest cohort (Leeds) was carried out adjusting for factors known to impact on survival. The results were then compared with data from nine smaller cohorts. The absence of any consensus MC1R alleles was associated with a significantly lower risk of death in the Leeds set (HR, 0.64; 95% CI, 0.46–0.89) and overall in the 10 data sets (HR, 0.78; 95% CI, 0.65–0.94) with some support from the nine smaller data sets considered together (HR, 0.83; 95% CI, 0.67–1.04). The data are suggestive of a survival benefit for inherited MC1R variants in melanoma patients.
doi:10.1111/j.1755-148X.2012.00982.x
PMCID: PMC3490389  PMID: 22325793
MC1R; survival analysis; MITF; melanoma; forest plot

Results 1-15 (15)