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Title: Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk.

Authors: Madeleine, Margaret M; Johnson, Lisa G; Smith, Anajane G; Hansen, John A; Nisperos, Brenda B; Li, Sue; Zhao, Lue-Ping; Daling, Janet R; Schwartz, Stephen M; Galloway, Denise A

Published In Cancer Res, (2008 May 1)

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.

PubMed ID: 18451182 Exiting the NIEHS site

MeSH Terms: Adolescent; Adult; Age Distribution; Aged; Carcinoma, Squamous Cell/epidemiology; Carcinoma, Squamous Cell/genetics*; Case-Control Studies; DNA Mutational Analysis; Female; Gene Frequency; Genetic Predisposition to Disease; HLA-A Antigens/analysis; HLA-A Antigens/genetics*; HLA-B Antigens/analysis; HLA-B Antigens/genetics*; HLA-C Antigens/analysis; HLA-C Antigens/genetics*; HLA-DQ Antigens/analysis; HLA-DQ Antigens/genetics*; HLA-DQ beta-Chains; HLA-DR Antigens/analysis; HLA-DR Antigens/genetics*; HLA-DRB1 Chains; Humans; Membrane Glycoproteins/analysis; Membrane Glycoproteins/genetics*; Middle Aged; Prevalence; Risk Factors; Sexual Partners; Smoking/epidemiology; Uterine Cervical Neoplasms/epidemiology; Uterine Cervical Neoplasms/genetics*

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