Abstract
Variation in human major histocompatibility genes may influence the risk of squamous cell cervical cancer (SCC) by altering the efficiency of the T-cell-mediated immune response to human papillomavirus (HPV) antigens. We used high-resolution methods to genotype human leukocyte antigen (HLA) class I (A, B, and Cw) and class II (DRB1 and DQB1) loci in 544 women with SCC and 542 controls. Recognizing that HLA molecules are codominantly expressed, we focused on co-occurring alleles. Among 137 allele combinations present at >5% in the case or control groups, 36 were significantly associated with SCC risk. All but one of the 30 combinations that increased risk included DQB1*0301, and 23 included subsets of A*0201-B*4402-Cw*0501-DRB1*0401-DQB1*0301. Another combination, B*4402-DRB1*1101-DQB1*0301, conferred a strong risk of SCC (odds ratio, 10.0; 95% confidence interval, 3.0-33.3). Among the six combinations that conferred a decreased risk of SCC, four included Cw*0701 or DQB1*02. Most multilocus results were similar for SCC that contained HPV16; a notable exception was A*0101-B*0801-Cw*0701-DRB1*0301-DQB1*0201 and its subsets, which were associated with HPV16-positive SCC (odds ratio, 0.5; 95% confidence interval, 0.3-0.9). The main multilocus associations were replicated in studies of cervical adenocarcinoma and vulvar cancer. These data confirm that T helper and cytotoxic T-cell responses are both important cofactors with HPV in cervical cancer etiology and indicate that co-occurring HLA alleles across loci seem to be more important than individual alleles. Thus, certain co-occurring alleles may be markers of disease risk that have clinical value as biomarkers for targeted screening or development of new therapies.
Highlights
Cervical cancer is the second most common cancer among women worldwide, with f500,000 new cases and >270,000 deaths occurring globally each year [1]
Consistent with other studies of cervical cancer, women with squamous cell cervical cancer (SCC) in this study had more sexual partners compared with women without cervical cancer and the cases were more frequently current smokers compared with controls (Table 1)
We found significantly elevated risks of SCC associated with three class I alleles (Table 2) that were present in >20% of the cases: A*0301 (OR, 1.4; 95% confidence intervals (95% CI), 1.1–1.9), B*4402 (OR, 1.9; 95% CI, 1.4–2.7), and Cw*0501 (OR, 1.6; 95% CI, 1.2–2.3)
Summary
Cervical cancer is the second most common cancer among women worldwide, with f500,000 new cases and >270,000 deaths occurring globally each year [1]. It is primarily caused by a common sexually transmitted pathogen, oncogenic human papillomavirus (HPV). Because HPV is a common infection in young women and cancer is a rare outcome, other factors such as individual immune response to the infection are likely necessary to promote persistent HPV infection and the development of increasingly severe cervical intraepithelial neoplasia that precedes invasive cervical cancer. An effective immune response may require optimal peptide presentation by both class I and class II molecules to activate efficient helper and effector T-cell responses to HPV. Subtle changes or impairment in T-cell responses may allow escape from immune surveillance or induction of immune anergy or tolerance to HPV peptides
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