Association of functional gene variants in the regulatory regions of COX-2 gene (PTGS2) with nonmelanoma skin cancer after organ transplantation

Background: Overexpression of cyclooxygenase-2 (COX-2), resulting in excessive prostaglandin production, has been observed in human epidermal keratinocytes after ultraviolet B injury, in squamous cell skin carcinoma (SCC), in actinic keratoses, and in the early stages of carcinogenesis in a wide variety of tissues. The dysregulation of COX-2 expression can in part be due to functional changes affecting regulatory elements in the promoter or 3′ untranslated region (UTR) of the gene. Two common polymorphisms (-765G→C, and -1195A→G) in the promoter region of the COX-2 gene (now PTGS2), and one common polymorphism in the 3′ UTR (8473T→C) have been described, and reported as associated with various malignancies. Objectives: To determine if common known polymorphisms in the regulatory region of the COX-2 gene (PTGS2) can be associated with nonmelanoma skin cancer (NMSC) predisposition after organ transplantation, to evaluate if cancer risks are associated with specific COX-2 gene (PTGS2) haplotypes containing these polymorphisms, and to identify possible new genetic polymorphisms in the proximal 5′ or 3′ regulatory regions of the gene associated with disease. Methods: The frequency of the three polymorphisms was determined in 240 Northern Italian transplant recipient patients (107 cases and 133 controls) with polymerase chain reaction-restriction fragment length polymorphism analysis. The proximal 5′ and 3′ regulatory regions of the gene were screened by heteroduplex analysis. Results: Stratification by age at transplant and type of tumours [SCC or basal cell carcinoma (BCC)] demonstrated that allele -765C represented a protective factor in BCC cases undergoing transplantation before 50 years of age (CC + CG vs. GG, Fisher exact test P = 0.003). One rare polymorphism, -62C→G, was detected in the 5′ flanking region. The allele frequency of -62G was 0.019, and no difference in genotype between cases and controls was observed. No other variants were found, suggesting that sequence variations in these regions are not likely to contribute to NMSC risk in this population. Haplotype analysis showed that the haplotype containing all major alleles represents a protective factor in patients with SCC undergoing transplantation after 50 years of age [P = 0.009; OR = 0.37 (0.18-0.79)] and that variant -1195A→G may represent a risk factor in this subgroup of patients [P = 0.01; OR = 4.77 (1.47-16.41)]. Haplotype analysis in patients with BCC revealed that variant -765C might be a protective factor in patients undergoing transplantation before 50 years of age. Variant 8473T→C, located in the 3′ UTR region of the gene, showed no association with NMSC risk after transplantation. Conclusions: COX-2 common variants -765G→C and -1195A→G appear to be associated with risk of NMSC, although in different ways in the SCC and BCC subgroups, indicating that environmental and genetic risk factors may play different roles in the outcome leading to these two phenotypes.