Carcinogenesis Advance Access published online on July 18, 2008
Carcinogenesis, doi:10.1093/carcin/bgn160
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A role for ultraviolet radiation immunosuppression in non-melanoma skin cancer as evidenced by gene-environment interactions
1 Department of Environmental Health, Harvard School of Public Health, Boston, Massachusetts
2 Section of Biostatistics and Epidemiology, Department of Community and Family Medicine, and the Norris Cotton Cancer Center, Dartmouth Medical School, Lebanon, New Hampshire
3 Section of Dermatology, Department of Medicine, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
4 Department of Pathology, Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire
5 Division of Epidemiology and Community Health, University of Minnesota Cancer Center, University of Minnesota School of Public Health, University of Minnesota Cancer Center, Minneapolis, Minnesota
* to whom reprint requests should be addressed: University of Minnesota Cancer Center, 554A Cancer Center Research Building, 420 Delaware Street SE, MMC 806, Minneapolis, MN 55455; phone 612-626-9887, fax 612-626-4842, email hhnelson{at}umn.edu
The genotoxic effects of ultraviolet radiation (UVR) are well-known causes of skin cancers; however, UVR also suppresses the immune system, decreasing the body's surveillance for tumor cells. In experimental systems, UVR immunosuppression is at least partially mediated through urocanic acid (UCA), an UVR-absorbing molecule in the stratum corneum. We tested the hypothesis that genetic variation in the histidase gene (HAL), which catalyzes the formation of UCA in the skin, modifies risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in a population-based study (914 BCC, 702 SCC, and 848 controls). We observed no evidence of a main gene effect for the HAL I439V polymorphism (rs7297245) and BCC or SCC. However, we found a HAL genotype-sunburn interaction in association with BCC (p for interaction = 0.040) and SCC (p for interaction = 0.018). A HAL genotype-SCC association was observed primarily among women (OR = 1.5, 95% CI 1.1-2.2), and among women, we found an interaction between HAL genotype and oral contraceptives use on SCC risk (p = 0.040). The variant HAL allele likewise appeared to modify the SCC risk associated with glucocorticoid steroid usage (p for interaction = 0.0004). In conclusion, our findings are a first step in determining the genetic underpinnings of UV immune suppression and have identified important new genetic interactions contributing to the etiology of skin cancer.
Key Words: polymorphism • UV-induced immunosuppression • skin cancer
Received April 2, 2008; revised June 27, 2008; accepted July 2, 2008.