IMMUNOGENETICS OF HPV-RELATED CANCERS

生殖器感染由人类乳头瘤病毒属(HPV型)引起，是宫颈疾病的必然原因 癌症和很大比例的外阴癌。越来越多的证据表明，乙型HPV属 类型有助于鳞状细胞皮肤癌(SCSC)的发展，尤其是器官 移植受者(OTR)。尽管人乳头瘤病毒癌蛋白影响的分子机制 肛门生殖器和SCSC的发育不同，这是一种免疫环境，允许病毒和/或新生 逃避宿主监视的肿瘤细胞可能在这些癌症的病因学中起着关键作用。我们的长期合作 目的是阐明免疫遗传因素在HPV相关癌症病因学中的作用。在第一个具体的 目的：我们将检验这样一种假设，即人们患宫颈癌和外阴癌的风险增加。 携带Toll样受体(TLR)途径相关基因的变异等位基因(TLR3、TLR4、TLR7、TLR9、 TICAM1、T1CAM2、TIRAP、IRAKI、IRAK4、TOLLIP、TRAF6、TBK1、IKBKE、IRF3)，这是 先天免疫反应。这个目标将使用资源DNA样本和来自人群的采访数据- 以宫颈鳞状细胞癌(n=391)、子宫腺癌(n=508)、鳞状细胞癌 外阴癌(n=)和人口控制(n=1,318)是在#年以前的供资期间积累的 该计划项目拨款。在第二个具体目标中，我们将检验这样一个假设，即 在携带与HPV免疫反应相关的基因的变异等位基因的人中，OTR增加， 肿瘤抗原和/或紫外线：人类白细胞抗原(HLA)(DRB1、DQB1、A、B、C和G)；TLR 途径(TLR4、TLR7、TICAM1、TICAM2、IRAKI、IRAK4、TOLLIP、TRAF6、TBK1、IKBKE、IRF3)， 免疫调节细胞因子(白介素10、白介素12A、白介素B、白介素6、干扰素和肿瘤坏死因子)与核苷酸切除修复 酶(XPB、XPC、XPD、XPF、XPG和ERCC1)。这一目标将使用DNA样本和其他数据 从项目1招募的250例SCSC病例和250名对照中获得。 经典的HLA-DRB1-DQB1，-A，-B，-C基因座，我们将通过以下方式捕捉基因组变异的主要模式 标签单核苷酸多态(Tag SNPs)的选择和检测。的分析方法 多位点基因数据将被用来评估与个体多态和 推断的单倍型。这个项目将提供关于遗传变异在免疫中的作用的新信息。 HPV相关癌症发生过程中的反应系统。 摘要：感染致癌的人类乳头瘤病毒(HPV)很常见，但有许多 感染者不会患上癌症。这项研究将确定一个人的基因构成 影响是否发生HPV相关癌症，并可能为此类癌症的发生提供线索 防止在未来发生。

Genital infection by genus alpha human papillomavirus (HPV) types is the necessary cause of cervical cancer and a large proportion of vulvar carcinomas. Accumulating evidence suggests that genus beta HPV types contribute to the development of squamous cell skin carcinoma (SCSC), particularly in organ transplant recipients (OTR). Although the molecular mechanisms through which HPV oncoproteins influence the development of anogenital and SCSC differ, an immunologic milieu that allows the virus and/or nascent tumor cells to escape host surveillance likely plays a key role in the etiology of these cancers. Our long-term goal is to clarify the role of immunogenetic factors in the etiology of HPV-related cancers. In the first specific aim, we will test the hypothesis that the risk of cervical and vulvar carcinoma is increased among persons carrying variant alleles of genes involved in the Toll-like receptor (TLR) pathway (TLR3, TLR4, TLR7, TLR9, TICAM1, T1CAM2, TIRAP, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), a key component of the innate immune response. This aim will use resourcesDNA specimens and interview data from population- based cases of squamous cell cervical cancer (n=391), cervical adenocarcinomas (n=508), squamous cell vulvar carcinomas (n=535), and population controls (n=1,318)accumulated in the prior funding periods of the Program Project Grant. In the second specific aim, we will test the hypothesis that the risk of SCSC in OTR is increased among persons carrying variant alleles of genes involved in the immune response to HPV, tumor antigens, and/or UV light: human leukocyte antigen (HLA) (DRB1, DQB1, A, B, C, and G); TLR pathway (TLR4, TLR7, TICAM1, TICAM2, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), immunomodulatory cytokines (IL10, IL12A, IL12B, IL6, IFNG and TNF), and nucleotide excision repair enzymes (XPB, XPC, XPD, XPF, XPG, and ERCC1). This aim will use DNA specimens and other data obtained from 250 SCSC cases and 250 controls recruited into Project 1. For the candidate genes other than the classical HLA-DRB1-DQB1, -A, -B, -C loci, we will capture the major patterns of genomic variation by choosing and assaying for tagging single nucleotide polymorphisms (tagSNPs). Analytic methods for multilocus genotype data will be used to estimate the associations with individual polymorphisms and inferred haplotypes. This project will provide new information about the role of inherited variation in immune response systems in the development of HPV-related cancers. LAY SUMMARY: Infection with cancer-causing human papillomaviruses (HPV) is common, but many infected persons do not develop cancer. This study will determine whether a person's genetic make-up influences whether HPV-related cancers occur, and could provide clues as to how such cancers might be prevented in the future.