Updated Field Synopsis and Systematic Meta-Analyses of Genetic Association Studies in Cutaneous Melanoma: The MelGene Database

We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10−8) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10−8<P<1 × 10−3. In supplementary meta-analyses derived from genome-wide association studies, one additional locus located 11 kb upstream of ARNT (chromosome 1q21) showed genome-wide statistical significance with CM. Our approach serves as a useful model in analyzing and integrating the reported germline alterations involved in CM

Melanocortin-1 receptor, skin cancer and phenotypic characteristics (M-SKIP) project

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 dev

Circulating insulin-like growth factor I in relation to melanoma risk in the European Prospective Investigation into Cancer and Nutrition

Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma

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

Interim Analysis of Phase 2 Results for Cemiplimab in Patients with Metastatic Basal Cell Carcinoma (mBCC) who Progressed on or are Intolerant to Hedgehog Inhibitors (HHIs)

Abstract not available

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.[Please see the Supplementary Note for acknowledgments.]This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.337

Primary Analysis of Phase 2 Results for Cemiplimab in Patients (pts) with Locally Advanced Basal Cell Carcinoma (laBCC) who Progress on or are Intolerant to Hedgehog Inhibitors (HHIs)

Abstract not available

An Epidemiological Update on Indoor Tanning and the Risk of Skin Cancers

Indoor tanning (sunbeds, solarium) uses artificial ultraviolet radiation (UVR) to stimulate cosmetic tanning of the skin. Indoor tanning has been officially classified as a human carcinogen in 2009 by the International Agency for Research on Cancer of the World Health Organization (WHO). The differences in the prevalence of sunbed use across countries and over the years highlight underlying legislative, climatic, and cultural differences. Indoor tanning-seeking behaviors may be driven by motivations for an appealing appearance, largely influenced by gender and age, and several misconceptions that a prevacation tan safeguards the skin, that sunbeds can be used to treat acne or to increase vitamin D, or that tanning is a healthy habit. This review provides an epidemiological update on the prevalence of sunbed use, who tends to use sunbeds and why, and details the current evidence on the association of sunbeds with skin cancers, including cutaneous melanoma, basal cell carcinoma (BCC), and cutaneous squamous cell carcinoma (cSCC). A statistically significant higher risk of cutaneous melanoma, BCC and cSCC with the use of sunbeds has been consistently demonstrated. This risk of skin cancer is even higher with the more frequent use of sunbeds, underscoring a dose&ndash;response relationship, and in those first exposed to sunbeds at a younger age. Preventive measures against sunbed use include legislation restricting sunbed use, educational campaigns to inform and discourage from indoor tanning, as well as using the internet, online advertising messages and the social media to reach larger audiences and to promote an untanned appearance

The value of screening in melanoma

The incidence of cutaneous melanoma has increased substantially in most white populations during the past several decades. Despite improvements in the early recognition of melanoma and the use of novel diagnostic techniques that enhance our diagnostic capabilities, disease-related mortality remains a significant public health issue. In the absence of effective treatment approaches for advanced disease, the best means for reducing deaths by melanoma are screening as well as professional and public education. The role of population-or community-based screening remains controversial, but evidence from self-selected screening campaigns, health care professional surveillance, and specialized pigmented lesions clinics underscores the value of screening and early detection programs, particularly in high-risk groups. Annual screening campaigns coupled with intense media promotion have become commonplace in many Countries, and despite their low yield of melanoma detection, the dissemination of educational material and information to the public during. these events is important in increasing public awareness. Future directions should include using screening campaigns to target middle-aged and older men and persons of lower socioeconomic status, Who stiffer most from the burden of the disease and its associated mortality. On a worldwide scale, comprehensive educational and screening campaigns should be implemented or intensified in underserved areas and geographic regions with lower survival rates, such as Eastern European Countries. A better understanding of the biology of the disease, already occurring with notable strides, will help us to define better those individuals who will benefit most from screening and early detection efforts. Technologic advances and new diagnostic modalities will afford a more reliable and vigilant Surveillance of high-risk individuals, whereas the wide use of the Internet will enhance the distribution of relevant information to the public with the ultimate goal of achieving a better control of melanoma. (C) 2009 Elsevier Inc. All rights reserved