638 Inverse genetic risk between cutaneous melanoma, basal cell carcinoma, squamous cell carcinoma and vitiligo

Abstract

Several epidemiological studies have reported an inverse association between vitiligo and skin cancers such as cutaneous melanoma, basal cell carcinoma and squamous cell carcinoma. There are conflicting reports whether this association is a consequence of increased immunosurveillance observed in vitiligo patients or rather a shared genetic contribution. The latter hypothesis however, is not currently sustained by available evidence. Herein, we compared 23 vitiligo-associated variants (P<5x10-8) from a recently published genome-wide association study and identified three variants—contained within the TYR, MC1R-DEF8, and RALY-EIF252-ASIP-ACHY-ITCH loci—that have been associated with increased risk for melanoma, basal cell carcinoma, and squamous cell carcinoma and a concurrent decreased risk for vitiligo. We then subjected GWAS summary statistics for vitiligo and each skin cancer to an unbiased two-sample mendelian randomization analysis. We observed a protective role for vitiligo in the development of cutaneous melanoma (effect size=-6.78x10-4; p=5.41x10-2), basal cell carcinoma (effect size=-1.29x10-3; p=1.77x10-3), and squamous cell carcinoma (effect size=-2.19-4; p=1.81x10-3). When the vitiligo-associated signature was subjected to the same analysis, a significantly increased protective relationship was observed for each skin cancer (melanoma effect size=-0.511; p=2.41x10-5; basal cell carcinoma effect size=-0.454; p=4.36x10-7; squamous cell carcinoma effect size=-0.489; p=5.59x10-10). Our results support a causal inverse genetic relationship between these skin cancers and vitiligo, and reveal potential therapeutic targets for the prevention and effective treatment of vitiligo-associated skin cancer.