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Polymorphisms in CTLA4 Confer Susceptibility to Nonmelanoma Skin Cancers

A genetic variant that confers excess risk for autoimmune disease may also protect against 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.

Comment: This information supports the concept, derived primarily from experimental animal models, that mutations in keratinocytes as well as UV-induced impairment of immune response are necessary for the development of sunlight-induced nonmelanoma skin cancers. These findings align with findings of higher renal cell carcinoma incidence in patients with the AA allele than in those with at least one G allele. When genetic profiles become part of standard practice, individuals with the AA genotype and a greater risk for nonmelanoma skin cancers can be urged to take more aggressive measures to protect against UV-induced skin cancers.

— Craig A. Elmets, MD

Published in Journal Watch Dermatology September 25, 2009

Citation(s):

Welsh MM et al. CTLA4 variants, UV-induced tolerance, and risk of non-melanoma skin cancer. Cancer Res 2009 Aug 1; 69:6158.

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