Association of variant -765G>C in the PTGS2 gene promoter with melanoma in Italian patients and its relation to gene expression in dermal fibroblasts.

Aim: The production of prostaglandins, especially prostaglandin E synthetase (PGE2) is hypothesized to influence carcinogenesis by promoting cell proliferation, inhibiting apoptosis, stimulating angiogenesis, and mediating immune suppression. Cyclooxygenase-2 (Cox-2), the inducible isoform of cyclooxygenase coded by the PTGS2 gene, is the key enzyme in the production of prostaglandins involved in inflammatory processes including cancer. In melanoma skin cancer, Cox-2 is overexpressed in primary malignant melanoma and in their corresponding metastases. Aim of this study was to investigate if polymorphisms -765G>C (rs20417), and -1195A>G (rs689466) in the PTGS2 gene impact on its expression in dermal fibroblasts and are associated with individual susceptibility to malignant cutaneous melanoma. Methods: Two hundred forty patients presenting melanoma and 342 control individuals were genotyped for polymorphisms -765G>C (rs20417) and -1195A>G (rs689466) by restriction fragment length polymorphism (PCR-RFLP) analysis. PTGS2 gene expression was performed by Real Time PCR using Sybr Green. Results: The allele -765C was associated with an increased prevalence of melanoma. No association of -1195A>G polymorphism was observed. Haplotype analysis of both variations showed that the haplotypes carrying the minor alleles were associated to a higher risk of melanoma (p=0.02). Expression analysis indicated that allele -765C is associated to a higher gene expression and thus could represent a risk allele by affecting the functionality of the promoter. Conclusion: In conclusion, variant -765G>C may be associated to malignant cutaneous melanoma with a low penetrance effect and this effect could be a consequence of altered gene expression.