MODULATION OF RISK AND PROGNOSIS OF CUTANEOUS MELANOMA BY VARIANTS IN JAK1, JAK2, STAT3 GENES

Background:The JAK/STAT signaling pathway supports the development, progression and metastatic potential of cutaneous melanoma (CM). The JAK1, JAK2, STAT3 proteins are coded by 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 single nucleotide variants (SNV) JAK1 (c.1648 + 1272G > A and c.991-27C > T), JAK2 (c.-1132G > T and c.-139G > A) and STAT3 (c.*1671T > C and c.-1937C > G) influence the risk and prognosis of CM. Methods: We evaluated 248 CM patients and 274 controls. Genotyping and gene expression were performed by real-time PCR and quantitative PCR, respectively. For the SNV considered of most interest in the study, the gene expression and luciferase assay were performedin a genetically modified SK-MEL-28. Differences between groups were assessed by the Fisher or chi-square test. Comparisons of gene expression and luciferase results were performed using t-tests or Mann-Whitney. The progression free survival and overall survival were obtained using the KaplanMeier curves and Cox analyses. Results: Individuals with STAT3 c.*1671TT and T allele, and STAT3 c.-1937CC genotype had 1.76 (P = 0.02), 1.42 (P = 0.02) and 1.67 (P = 0.02) 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 (P = 0.001) fold increased risk of CM than those with other haplotypes. Finally, in a genetically modified SK-MEL-28 of STAT3 c.-1937C > G, we observed a 30% increase in the promoter activity and mRNA in cells with CC genotype compared with GG genotype. The median follow-up of CM patients was 93 months (variation: 5-221 months). In univariate Cox analysis, patients with the JAK1 c.1648+1272GG and JAK1 c.991-27CC isolated genotypes and JAK1 c.1648+1272GG plus JAK1 c.991-27CC combined genotype had 1.78, 1.71 and 1.82 more chances of presenting progression of disease, respectively. Patients with JAK1 c.1648+1272GG plus JAK1 c.991-27CC plus JAK2 c.-1132GG plus JAK2 c.-139GG combined genotype had 2.11 more chance of presenting disease progression than others. Conclusions: The data present, for the first time, preliminary evidence that inherited abnormalities in the JAK/STAT pathway, related to JAK1 and STAT3 gene, alter the risk, gene expression and prognosis of CM patients. Funding support: CAPES, FAPESP.

Publication History

Article published online:
23 October 2019