Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk
Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk
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DOI：
10.1158/0008-5472.can-07-6471
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发表时间：
2008-05-01
期刊：
影响因子：
11.2
通讯作者：
Galloway, Denise A.
中科院分区：
文献类型：
--
作者：
Madeleine, Margaret M.;Johnson, Lisa G.;Galloway, Denise A.
人类主要组织相容性基因的变异可能通过改变T细胞介导的对人乳头瘤病毒（HPV）抗原的免疫应答的效率来影响鳞状细胞宫颈癌（SCC）的风险。我们使用高分辨率方法对544名SCC患者和542名对照者的人类白细胞抗原（HLA）I类（A、B和Cw）和II类（DRB 1和DQB 1）位点进行基因分型。认识到HLA分子是共显性表达的，我们专注于共发生的等位基因。在病例组或对照组中存在>5%的137个等位基因组合中，36个与SCC风险显著相关。30种增加风险的组合中，除一种外，所有组合都包括DQB 1 *0301，23种组合包括A*0201-B*4402-Cw*0501-DRB 1 *0401-DQB 1 *0301的子集。另一种组合，B*4402-DRBI* 1101 DQBI *0301，赋予SCC的强风险（比值比，10.0; 95%置信区间，3.0-33.3）。在六种降低SCC风险的组合中，有四种包括Cw*0701或DQB 1 *02。对于含有HPV 16的SCC，大多数多位点结果相似;一个值得注意的例外是A*0101-B*0801-Cw*0701-DRB 1 *0301-DQB 1 *0201及其子集，它们与HPV 16阳性SCC相关（比值比，0.5; 95%置信区间，0.3-0.9）。在宫颈腺癌和外阴癌的研究中重复了主要的多位点关联。这些数据证实，辅助性T细胞和细胞毒性T细胞反应都是宫颈癌病因学中HPV的重要辅助因子，并表明跨基因座的共同发生的HLA等位基因似乎比单个等位基因更重要。因此，某些共现的等位基因可能是疾病风险的标志物，其具有作为靶向筛选或开发新疗法的生物标志物的临床价值。
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-DRBI*1101DQBI*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.