Program in Public Health, University of California Irvine, Irvine, CA 92697, USA.
Department of Neurobiology and Behavior, School of Biological Sciences, University of California Irvine, Irvine, CA 92697, USA.
Int J Mol Sci. 2020 Mar 5;21(5):1776. doi: 10.3390/ijms21051776.
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, = 0.006) in men but a significant opposite effect in women (OR = 0.15, 95% CI: 0.018, 0.86, = 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, = 0.008) and no effect in women. Results from the current study are warranted for further validation.
性别在皮肤黑色素瘤发病率上的差异的机制尚不清楚。类固醇激素（包括雌激素）长期以来一直被认为与黑色素瘤的发生有关，但结论存在争议。雌激素受体（ERs）和胰岛素样生长因子 1 受体（IGF1R）在癌症发展中表现出广泛的相互作用，但 ER/IGF1R 网络如何影响黑色素瘤目前尚不清楚。在这里，我们研究了 ER/IGF1R 网络中选定的单核苷酸多态性（SNP）与黑色素瘤的关联。国际基因、环境和黑色素瘤（GEM）队列的一部分被用作发现集，基因环境关联研究倡议（GENEVA）数据集作为验证集。基于与其他恶性疾病的关联，我们选择了 ESR1、ESR2、IGF1 和 IGF1R 中的 13 个单核苷酸多态性（SNP）变体进行候选基因关联分析。在 Benjamini-Hochberg 多重比较校正后，IGF1 中的 rs1520220 和 IGF1R 中的 rs2229765 变体与 GEM 数据集中的黑色素瘤风险显著相关，尽管它们在 GENEVA 数据集中没有得到验证。这种差异可能是由于 GEM 患者的多种黑色素瘤特征所致。我们进一步对 GEM 数据集中 IGF1 和 IGF1R SNPs 的性别差异进行了分析。IGF1 rs1520220 的 GG 表型（隐性模型）在男性中表现出黑色素瘤的风险增加（OR = 8.11，95%CI：2.20，52.5， = 0.006），而在女性中则表现出显著相反的效果（OR = 0.15，95%CI：0.018，0.86， = 0.045）。IGF1R rs2229765 的 AA 基因型（隐性模型）在男性中表现出显著的保护作用（OR = 0.24，95%CI：0.07，0.64， = 0.008），而在女性中则没有作用。目前的研究结果有待进一步验证。
