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

• Immunogenetic variation may contribute to HPV clearance or progression.
• T-helper pathway variants may impact risk of HPV-related cancers.
• We report novel associations between Th17 genes and cervical and vulvar cancers.

ObjectivePersistent 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.MethodsThe 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.ResultsStatistically 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.ConclusionsWe 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.