A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers

Abstract Objective Persistent infection with oncogenic human papillomavirus (HPV) is known to be the necessary cause of cervical cancer and a majority of vulvar cancers. Persistent HPV infections must evade host immune responses, including cytokines released by activated T-helper (Th) cells. In this study, we investigated the risk of cervical and vulvar cancers associated with common genetic variations in 560 tagging single-nucleotide polymorphisms (SNPs) in candidate cytokine genes. Methods The study included 399 invasive squamous cell carcinomas (SCCs) and 502 in situ or invasive adenocarcinomas (AC) of the cervix; 357 in situ or invasive vulvar SCC; and 1109 controls from the Seattle-area case–control studies of HPV-related cancers. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using a log additive model, with adjustment for multiple testing. Results Statistically significant risks were observed for HPV16-containing SCC of the cervix with the variant allele rs879576 in IL17RA and rs2229094 in TNF [OR, 95% CI and multiple-testing corrected p: 1.91 (1.30–2.79), p=0.018 and 0.61 (0.45–0.83), p=0.02, respectively]. We also observed significantly increased risk of HPV-positive vulvar cancers associated with variant alleles in CSF2 (rs25882 and rs27438, 26–28% increased risk) and IL-12B (rs2569254 and rs3181225, 40–41% increased risk) genes. Conclusions We found that variation in several Th-cytokine genes is significantly associated with cervical and vulvar cancer risk. The strong association between these HPV-related cancers and common variation in cytokine genes in the Th1 and Th17 pathways may be important for development of new therapies.