KIR gene content variation and risk of vulvar and cervical cancer: a population-based case-control study

Thesis (Ph.D.)--University of Washington, 2013The killer-cell immunoglobulin-like receptors (KIR) bind to MHC class I molecules that have been associated with risk of cervical and vulvar cancer. We investigated whether variation in KIR gene content was associated cervical and vulvar cancer in a population-based case-control study of women from Washington state. Study participants included 498 controls, 358 vulvar cancer cases, and 666 cervical cancer cases, including 227 squamous cell carcinomas, 419 adenocarcinomas, and 20 adenosquamous carcinomas. Controls were matched to cases on age and geographic region of residence and analyses were limited to whites to reduce the potential for bias due to population stratification. We found no associations between the presence of individual KIR genes and either vulvar cancer or all histologies of cervical cancer pooled. Three KIR genes were associated with cervical adenocarcinoma, including 2DS2 (OR 0.74, 95% CI 0.56-0.97), 2DL2 (OR 0.74, 95% CI 0.57-0.98), and 2DS3 (OR 0.72, 95% CI 0.53-0.98), though a permutation test provided no indication that these associations were more extreme than would be expected due to chance. These three KIR genes are among the centromeric haplotype B (CenB) KIR genes, though 2DS3 also occurs among the telomeric haplotype B KIR. The presence of CenB was associated with lower risk of cervical adenocarcinoma (OR 0.74, 95% CI 0.56-0.97). The presence of 2DS2 combined with one or more copies of its ligand, HLA-C group 1 alleles, defined by an asparagine residue at position 80, was associated with lower risk of cervical adenocarcinoma (OR 0.75, 95% CI 0.57-0.99). Tumor samples were tested for HPV DNA, and in polytomous logistic regression model we found that 3DS1 was associated with HPV 18-positive but not HPV 16-positive cervical adenocarcinoma. In conclusion, our study does not provide strong evidence that KIR gene content is related to risk of either vulvar or cervical cancer, all histologies pooled. Subgroup analyses suggest that CenB KIRs may contribute to lower risk of cervical adenocarcinoma, especially for cancers caused by HPV 18. This study contributes to research that aims to clarify the role of immunogenetic variation in determining why some women exposed to HPV develop cervical or vulvar cancer