BackgroundThe JAK/STAT signaling pathway supports the development, progression and metastatic potential of cutaneous melanoma (CM). In normal cells the activation of STAT3 is rapid and transient, but in abnormal melanocytes the activation of the protein occurs in a constitutive manner favoring tumor expansion. STAT3 is coded by the polymorphic gene in humans and thus it is possible that normal individuals show inherited differences in pathway functionality. The aim of the study was to evaluate whether STAT3 c.*1671T>C and STAT3 c.-1937C>G variants influence the risk of CM patients and its functional consequences.MethodsWe evaluated 248 MC patients and 274 controls. DNA was analyzed by real-time polymerase chain reaction (PCR) for genotyping. Luciferase assay and gene expression in a genetically modified SK-MEL-28 melanoma cell line to present the STAT3 c.-1937C>G ancestral and variant genotypes were realized in study. Differences between groups were assessed by the Fisher or chi-square test. Comparisons of luciferase and gene expression were performed using t-tests and ANOVA or Mann-Whitney and Kruskal-Wallis tests.ResultsIndividuals with STAT3 c.*1671TT and T allele, and STAT3 c.-1937CC genotype had 1.76 (95% CI: 1.08-2.85, P = 0.02), 1.42 (95% CI: 1.03-1.96, P = 0.02) and 1.67 (95% CI: 1.06-2.63, P = 0.02)-fold increased risks of CM than individuals with the other genotypes and allele, respectively. Individuals with TC haplotype of the STAT3 variants were at 1.70 (95% CI: 1.22-2.36, P = 0.001)-fold increased risk of CM than those with other haplotypes. In a genetically modified melanoma cell line to present the distinct genotypes of STAT3 c.-1937C> G, we observed a 30% increase in the promoter activity of the gene and increase of mRNA in cells with the CC genotype compared to those with the GG genotype.ConclusionsThe data present, for the first time, preliminary evidence that inherited abnormalities in the JAK/STAT pathway, related to STAT3 gene, alter the CM risk. These results may contribute to identify individuals at high risk for CM, who deserve special measures for prevention or early diagnosis.Legal entity responsible for the studyThe authors.FundingFAPESP and CAPES.DisclosureAll authors have declared no conflicts of interest.