Polymorphisms in CTLA4 Confer Susceptibility to Nonmelanoma Skin Cancers

Nonmelanoma skin cancers are highly immunogenic, but evidence suggests that exposure to ultraviolet radiation suppresses host antitumor immune responses. UV-induced immune suppression is due, at least in part, to production of excessive numbers of regulatory T-lymphocytes (Treg). Treg cells express the protein CTLA4, which is required for both their activation and their function. A polymorphism in an untranslated region of the gene that encodes for CTLA4 confers disease susceptibility to certain autoimmune diseases: Individuals with the GG or AG genotype at the CT60 locus are more likely to develop type 1 diabetes, autoimmune thyroid disease, and Graves disease than individuals with the AA genotype. Because of the exaggerated immune response associated with autoimmune disease, these investigators examined whether the CTLA4 polymorphism that increases autoimmune susceptibility might confer resistance to nonmelanoma skin cancers.

Once age, gender, skin type and lifetime number of severe sunburns were controlled for, subjects who had the GG genotype were less likely than those with the AA genotype to develop basal cell or squamous cell carcinoma (odds ratio for each type, 0.7; 95% confidence intervals, 0.5–1.0). No difference in susceptibility was seen in the AG heterozygotes. The decrease in BCC susceptibility was greatest in those with histories of severe sunburn: Among participants with two or more severe sunburns, the ORs for BCC were 0.5 in GG carriers and 0.6 in AG carriers.