Madeleine, Margaret M. and Johnson, Lisa G. and Smith, Anajane G. and Hansen, John A. and Nisperos, Brenda B. and Li, Sue and Zhao, Lue-Ping and Daling, Janet R. and Schwartz, Stephen M. and Galloway, Denise A. (2008) Comprehensive Analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 Loci and Squamous Cell Cervical Cancer Risk. Cancer Research, 68 (9). pp. 3532-3539. ISSN 1538-7445
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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.
| Item Type: | Article or Abstract |
|---|---|
| Additional Information: | This article is available to subscribers only via the URL above for the first 12 months post-publication. |
| DOI: | 10.1158/0008-5472.CAN-07-6471 |
| PubMed ID: | 18451182 |
| NIHMSID: | NIHMSID85424 |
| PMCID: | PMC2662593 |
| Grant Numbers: | R01 CA112512-03, P01 CA042792-19A1, P30 ES007033-13 |
| Keywords or MeSH Headings: | Adolescent; Adult; Age Distribution; Aged; Carcinoma, Squamous Cell/epidemiology/*genetics; Case-Control Studies; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-A Antigens/analysis/*genetics; HLA-B Antigens/analysis/*genetics; HLA-C Antigens/analysis/*genetics; HLA-DQ Antigens/analysis/*genetics; HLA-DR Antigens/analysis/*genetics; Humans; Membrane Glycoproteins/analysis/*genetics; Middle Aged; Prevalence; Risk Factors; Sexual Partners; Smoking/epidemiology; Uterine Cervical Neoplasms/epidemiology/*genetics |
| Subjects: | Diseases > Solid tumors > Cervical cancer Cellular and Organismal Processes > Immune Response Molecules > Antigens > HLA antigens |
| Depositing User: | Library Staff |
| Date Deposited: | 02 Apr 2009 18:34 |
| Last Modified: | 14 Feb 2012 14:42 |
| URI: | http://authors.fhcrc.org/id/eprint/215 |
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