Abstract
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.
Highlights
According to the Surveillance, Epidemiology, and End Results Program (SEER, National Cancer Institute) in their 2019 Annual Report [1], the incidence of cutaneous melanoma (CM) increased in both men and women in the US between 2011 and 2015
The family history of melanoma was higher in the controls than in the cases in the Gene Environment Association Studies Initiative (GENEVA) dataset (63.4% vs. 32.5%, p < 0.0001)
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Summary
According to the Surveillance, Epidemiology, and End Results Program (SEER, National Cancer Institute) in their 2019 Annual Report [1], the incidence of cutaneous melanoma (CM) increased in both men and women in the US between 2011 and 2015. The incidence rates are higher in older men (> ~ 50 years) but lower in younger men as compared to women of the same ages [5,7]. Pregnant women with a CM diagnosis usually showed poorer prognoses [11]. It is still controversial whether oral contraceptives were associated with an increased risk of melanoma or not [12,13,14]
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