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Cervical and Vulvar Cancer Risk in Relation to the Joint Effects of Cigarette Smoking and Genetic Variation in Interleukin 2

¹ Program in Epidemiology, Division of Public Health Sciences, ² Program in Immunogenetics, Division of Clinical Research, and ³ Program in Cancer Biology, Divisions of Human Biology and Public Health Sciences, Fred Hutchinson Cancer Research Center, ⁴ Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington; and ⁵ Division of Cancer Prevention and Control Research, University of California at Los Angeles School of Public Health and Jonsson Comprehensive Cancer Center, Los Angeles, California

Requests for reprints: Shehnaz K. Hussain, University of California at Los Angeles Division of Cancer Prevention and Control Research, School of Public Health and Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South A2-125 CHS, Box 956900, Los Angeles, CA 90095-6900. Phone: 310-825-8165; Fax: 310-206-3566. E-mail: skhussain{at}ucla.edu

Cigarette smoking is an established cofactor to human papillomavirus (HPV) in the development of cervical and vulvar squamous cell carcinoma (SCC), and may influence risk through an immunosuppressive pathway. Genetic variation in interleukin 2 (IL2), associated in some studies with the inhibition of HPV-targeted immunity, may modify the effect of smoking on the risk of HPV-related anogenital cancers. We conducted a population-based case-only study to measure the departure from a multiplicative joint effect of cigarette smoking and IL2 variation on cervical and vulvar SCC. Genotyping of the four IL2 tagSNPs (rs2069762, rs2069763, rs2069777, and rs2069778) was done in 399 cervical and 486 vulvar SCC cases who had been interviewed regarding their smoking history. Compared with cases carrying the rs2069762 TT genotype, we observed significant departures from multiplicativity for smoking and carriership of the TG or GG genotypes in vulvar SCC risk [interaction odds ratio (IOR), 1.67; 95% confidence interval (CI), 1.16-2.41]. Carriership of one of three diplotypes, together with cigarette smoking, was associated with either a supramultiplicative (TGCT/GGCC; IOR, 2.09; 95% CI, 0.98-4.46) or submultiplicative (TTCC/TGTC; IOR, 0.37; 95% CI, 0.16-0.85 or TGCT/TGCC; IOR, 0.37; 95% CI, 0.15-0.87) joint effect in vulvar cancer risk. For cervical SCC, departure from multiplicativity was observed for smokers homozygous for the rs2069763 variant allele (TT versus GG or GT genotypes; IOR, 1.87; 95% CI, 1.00-3.48), and for carriership of the TTCC/TTCC diplotype (IOR, 2.08; 95% CI, 1.01-4.30). These results suggest that cervical and vulvar SCC risk among cigarette smokers is modified by genetic variation in IL2. (Cancer Epidemiol Biomarkers Prev 2008;17(7):1790–9)