In order to explore melanoma risk factors through gender-, age-, race-, and site-specific incidence rates, malignant melanoma cases from the Caucasian whites and non-whites were retrieved from the US SEER database. Age-standardized, age-, and site-specific tumor rates were calculated. All races and both genders showed positive annual average percentage changes (AAPCs) over the years, but AAPCs varied at different body sites, with men’s trunk exhibiting the fastest increase. Non-whites were diagnosed at a significantly younger age than whites and showed a trend towards fewer gender differences in the age of diagnosis. However, non-whites and whites showed a similar pattern of age-specific gender differences in the incidence rate ratios. A consistent spiked difference (female vs. male, incidence rate ratio (IRR) >2) was observed at or near the age of 20–24 in all race groups and at all body sites. The highest female vs. male IRR was found in the hip and lower extremities, and the lowest IRR was found in the head and neck region in all races. These race-, gender-, and site-dependent differences suggest that age-associated cumulative sun exposure weighs significantly more in late-onset melanomas, while genetics and/or pathophysiological factors make important contributions to early-onset melanomas.

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.

Our results highlight the importance of gender as one of the melanoma risk factors beyond traditional UV radiation, which warrants further investigation and may provide a base for an improved prevention strategy.

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.

Patients with type 1 diabetes mellitus are associated with impairment in vitamin A metabolism. This study evaluated whether treatment with retinoic acid, the biologically active metabolite of vitamin A, can ameliorate diabetes. All-trans retinoic acid (atRA) was used to treat streptozotocin (STZ)-induced diabetic mice which revealed atRA administration ameliorated blood glucose levels of diabetic mice. This hyperglycemic amelioration was accompanied by an increase in the amount of β cells co-expressed Pdx1 and insulin and by restoration of the vascular laminin expression. The atRA-induced production of vascular endothelial growth factor-A from the pancreatic islets was possibly the key factor that mediated the restoration of islet vascularity and recovery of β-cell mass. Furthermore, the combination of islet transplantation and atRA administration significantly rescued hyperglycemia in diabetic mice. These findings suggest that vitamin A derivatives can potentially be used as a supplementary treatment to improve diabetes management and glycemic control.

Background/Objectives: Pediatric melanoma is rare and remains poorly characterized, especially in racial/ethnic minorities of whom Hispanics are the largest and fastest growing in the United States. The health care burden of melanoma in Hispanics, who often present with more advanced disease, is rising and has even been called an early epidemic in California. We sought to document key clinicopathologic features of melanoma in Hispanic pediatric patients and to compare these parameters to pediatric non-Hispanic whites (NHWs) under the a priori hypothesis that Spitzoid melanomas occur in greater proportions in Hispanics.Methods: Single-institution cross-sectional study of pediatric melanoma cases (age < 20 years) with Hispanic stratification and comparison with matched Surveillance, Epidemiology, and End Results (SEER) data from the same time frame .Results: Of our 61 institutional cases of pediatric melanoma, Hispanics (11), compared with NHWs (40), presented significantly younger (11.7 years, 95% CI: 2.77-8.00 years; P = .001), with lower limb predominance (46%; P < .05), mostly Spitzoid melanomas (82%; P < .05), and thicker tumors (2.34 mm, CI: 0.26-2.19 mm; P < .05).Similarly, SEER data (2499 cases) showed greater proportions of childhood/pre-pubertal adolescent melanomas (<15 years), lower limb involvement, Spitzoid subtype (36.5% vs 22.5% in NHWs; P = .001), and advanced (regional/distant) disease stages in Hispanics (212) compared with NHWs (2197).Conclusions: Pediatric melanomas may present differently in Hispanics, and heightened awareness/lower threshold to biopsy high-risk Spitzoid tumors on the lower limb may be warranted. Further investigations are needed to aid prevention and early detection in a vulnerable minority population less likely to seek outpatient dermatology specialty care.

Background: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and post-zygotic mosaicism (PZM) is critically needed for risk assessment and management. Methods: Participants in the Li Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq® assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. Results: Among 134 participants there was a significant difference for the age at diagnosis (p=&lt;0.001), component cancers (p=0.007), and clinical testing criteria (p=&lt;0.001), comparing germline vs PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed paraffin imbedded tissues demonstrated low variance (standard error 3%; p = 0.993) for TP53 variant allele fraction, with no significant difference (p=0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in 7, ACE for 25 and 3 were indeterminate. Additional CH variants were detected in 6 ACE and 2 germline cases. Conclusions: We demonstrated an effective approach and tools for discerning germline TP53 status. Impact: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.

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