Background Cutaneous melanoma (CM) incidence rates continue to increase, and the reasons are unknown. Previously, we reported a unique age-specific gender difference in melanoma that suggested additional causes other than solar UV radiation. Objective This study attempted to understand whether and how UV radiation differentially impacts the CM incidence in men and women. Methods CM data and daily UV index (UVI) from 31 cancer registries were collected for association analysis. A second dataset from 42 states of the U.S.A. was used for validation. Results There was no association between log-transformed female CM rates and levels of UVI but there was a significant association between male rates and UVI and a significant association between overall rates and UVI. The 5 year age-specific rate-UVI association levels (represented by Pearson’s coefficient ρ) increased with age in men, but age-specific ρ levels remained low and unchanged in women. The significant rate-UVI association in men and non-association in women was validated in the US white population. Limitations Confounders including temperature and latitude are difficult to separate from UVI Conclusions: Ambient UVI appears to be associated with melanoma incidence in males but not in females.

Recent studies have shown that ultraviolet (UV)-induced chemiexcitation of melanin fragments leads to DNA damage; and chemiexcitation of melanin fragments requires reactive oxygen species (ROS), as ROS excite an electron in the melanin fragments. In addition, ROS also cause DNA damages on their own. We hypothesized that ROS producing and metabolizing enzymes were major contributors in UV-driven melanomas. In this case-control study of 349 participants, we genotyped 23 prioritized single nucleotide polymorphisms (SNPs) in nicotinamide adenine dinucleotide phosphate (NADPH) oxidases 1 and 4 (NOX1 and NOX4, respectively), CYBA, RAC1, superoxide dismutases (SOD1, SOD2, and SOD3) and catalase (CAT), and analyzed their associated melanoma risk. Five SNPs, namely rs1049255 (CYBA), rs4673 (CYBA), rs10951982 (RAC1), rs8031 (SOD2), and rs2536512 (SOD3), exhibited significant genotypic frequency differences between melanoma cases and healthy controls. In simple logistic regression, RAC1 rs10951982 (odds ratio (OR) 8.98, 95% confidence interval (CI): 5.08 to 16.44; p < 0.001) reached universal significance (p = 0.002) and the minor alleles were associated with increased risk of melanoma. In contrast, minor alleles in SOD2 rs8031 (OR 0.16, 95% CI: 0.06 to 0.39; p < 0.001) and SOD3 rs2536512 (OR 0.08, 95% CI: 0.01 to 0.31; p = 0.001) were associated with reduced risk of melanoma. In multivariate logistic regression, RAC1 rs10951982 (OR 6.15, 95% CI: 2.98 to 13.41; p < 0.001) remained significantly associated with increased risk of melanoma. Our results highlighted the importance of RAC1, SOD2, and SOD3 variants in the risk of melanoma.

The mechanism of gender disparity in cutaneous melanoma incidence remains unclear. Steroid hormones including estrogens have long been implicated in the course of melanoma, but the conclusion is controversial. Estrogen receptors (ERs) and insulin-like growth factor 1 receptor (IGF1R) show extensive crosstalk in cancer development, but how the ER/IGF1R network impacts melanoma is currently unclear. Here we studied the melanoma associations of selected SNPs from the ER/IGF1R network. Part of the International Genes, Environment, and Melanoma (GEM) cohort was used as a discovery set, and the Gene Environment Association Studies Initiative (GENEVA) dataset served as a validation set. Based on the associations with other malignant disease conditions, thirteen single nucleotide polymorphism (SNP) variants in ESR1, ESR2, IGF1, and IGF1R were selected for candidate gene association analyses. The rs1520220 in IGF1 and rs2229765 in IGF1R variants were significantly associated with melanoma risk in the GEM dataset after Benjamini-Hochberg multiple comparison correction, although they were not validated in the GENEVA set. The discrepancy may be caused by the multiple melanoma characteristics in the GEM patients. Further analysis of gender disparity was carried out for IGF1 and IGF1R SNPs in the GEM dataset. The GG phenotype in IGF1 rs1520220 (recessive model) presented an increased risk of melanoma (OR = 8.11, 95% CI: 2.20, 52.5, p = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, p = 0.045). The AA genotype in IGF1R rs2229765 (recessive model) showed a significant protective effect in men (OR = 0.24, 95% CI: 0.07, 0.64, p = 0.008) and no effect in women. Results from the current study are warranted for further validation.

e20012 Background: UV radiation has been considered the major environmental causative factor for melanoma. Our previous limited epidemiologic study suggested additional causative factors for early age onset melanoma in females. Methods: Melanoma and non-melanoma skin cancer case and population information were retrieved from various cancer registries and public domains. Age-specific and age-standardized incidence rates were calculated and compared between genders and age groups; and correlated with average daily UV index. Results: The current study further compared the age and gender-specific incidence rates for melanoma and non-melanoma skin cancer (NMSC) from the Netherlands (N), UK and Nordic (NOR) countries, and confirmed a peak gender difference at age 20-24 (the peak age for pregnancy) for melanoma in all countries examined(N,