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1.  On the Interplay of Telomeres, Nevi and the Risk of Melanoma 
PLoS ONE  2012;7(12):e52466.
The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations.
doi:10.1371/journal.pone.0052466
PMCID: PMC3531488  PMID: 23300679
2.  MC1R variants predisposing to concomitant primary cutaneous melanoma in a monozygotic twin pair 
BMC Medical Genetics  2012;13:81.
Background
Concomitant primary cutaneous melanoma in monozygotic twins has been reported in only two pairs but in neither of them genetic analysis was performed. Two high-penetrance susceptibility genes, CDKN2A and CDK4 and one low-penetrance gene, MC1R, are well-defined genetic risk factors for melanoma. MITF has been recently identified as a novel intermediate risk melanoma-predisposing gene.
Case presentation
We describe the extraordinary occurrence of a primary cutaneous invasive melanoma in two 44-year-old identical, female twins, on the same body site within 30 days of each other and report for the first time the genetic analysis of melanoma susceptibility genes in both twins. Data on characteristics of the twins were collected through a standardized questionnaire and skin examination. Exons 1α, 1β, 2 and 3 of CDKN2A, exon 2 of CDK4, the entire open reading frame of MC1R and the recently described MITF c.952 G > A (p.Glu318Lys) variant were investigated by direct sequencing. Sequencing analysis of the high-penetrance susceptibility genes showed no changes in CDKN2A and in exon 2 of the CDK4 gene. Both patients were heterozygous for the same CDKN2A UTR c.*29C > G variant. Interestingly, the same two heterozygous variants of the MC1R were identified in both twins: the c.451C > T (p.Arg151Cys) and the c.456C > A (p.Tyr152*) variants. Neither patient showed the c.952 G > A (p.Glu318Lys) substitution in the MITF gene.
Conclusions
Identification of two high-risk MC1R variants in our identical twins in the absence of CDKN2A and CDK4 mutations highlights the contribution of low penetrance genes, such as MC1R, in melanoma susceptibility.
doi:10.1186/1471-2350-13-81
PMCID: PMC3483249  PMID: 22978401
Melanoma; Monozygotic twins; CDKN2A; CDK4; MC1R; MITF; Genetic susceptibility
3.  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
4.  A cost–utility analysis of etanercept for the treatment of moderate-to-severe psoriasis in Italy 
Introduction:
Biologic therapies have proven efficacious for patients with moderate-to-severe psoriasis. However, their economic value compared with standard of care in Italy has not been explored. This study estimates the cost-effectiveness of intermittent therapy with etanercept in patients with moderate-to-severe plaque-type psoriasis in comparison with nonsystemic therapy in Italy.
Methods:
This study employs cost–utility analysis using a Markov model adapted from the British “York model”. It compares the cost per quality-adjusted life-year (QALY) of intermittent etanercept (25 mg twice weekly) versus nonsystemic therapy. Data on efficacy and changes in quality of life were derived from three etanercept clinical trials. Direct costs of treating psoriasis patients, including hospitalizations and dermatology clinic visits, were taken from an Italian cost-of-illness study. Extrapolations were made to evaluate the cost-effectiveness of intermittent etanercept versus nonsystemic therapy over a period of ten years.
Results:
For the group of patients with moderate and severe plaque psoriasis (initial Psoriasis Area and Severity Index [PASI ≥ 10]) the incremental cost-effectiveness ratio (ICER) for etanercept compared with nonsystemic therapy was €33,216/QALY; for the group of patients with severe psoriasis (PASI ≥ 20), the ICER was €25,486/QALY.
Conclusions:
Within the Italian health care system, intermittent etanercept is a cost-effective therapeutic option compared with nonsystemic therapy for the group of patients with moderate and severe plaque psoriasis. For patients with PASI ≥ 20, cost-effectiveness of etanercept is even greater.
PMCID: PMC3169985  PMID: 21935307
cost-utility; cost-effectiveness; psoriasis; etanercept; Markov model
5.  Nucleotide diversity and population differentiation of the Melanocortin 1 Receptor gene, MC1R 
BMC Genetics  2008;9:31.
Background
The melanocortin 1 receptor gene (MC1R) is responsible for normal pigment variation in humans and is highly polymorphic with numerous population-specific alleles. Some MC1R variants have been associated with skin cancer risk.
Results
Allele frequency data were compiled on 55 single nucleotide polymorphisms from seven geographically distinct human populations (n = 2306 individuals). MC1R nucleotide diversity, π, was much higher (10.1 × 10-4) than in other genes for all subjects. A large degree of population differentiation, determined by FST, was also present, particularly between Asia and all other populations, due to the p.R163Q (c.488 G>A) polymorphism. The least amount of differentiation was between the United States, Northern Europe, and Southern Europe. Tajima's D statistic suggested the presence of positive selection in individuals from Europe.
Conclusion
This study further quantifies the degree of population-specific genetic variation and suggests that positive selection may be present in European populations in MC1R.
doi:10.1186/1471-2156-9-31
PMCID: PMC2324112  PMID: 18402696
6.  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

Results 1-6 (6)