Molecular epidemiology of cervical adenocarcinoma

描述（由申请人提供）：本项目的总体目标是通过研究宫颈腺癌和腺鳞癌（以下称为腺癌）的病毒病因学和编码某些人类白细胞抗原（HLA）单倍型的基因，提高对宫颈腺癌和腺鳞癌的生物学认识。长期目标是为这种疾病提出合理的预防战略。我们的主要具体目标是：1）估计腺癌的相对风险，作为HPV存在的总体函数和作为首次检测到人乳头瘤病毒（HPV）感染后时间的函数; 2）评估持续性和/或高初始HPV 16/18/45病毒载量是否是腺癌的决定因素; 3）评估某些HLA单倍型是否与腺癌风险相关，以及该关联是否通过较高的病毒载量和/或HPV 16/18/45的持续性介导。该项目将建立在以前两项研究宫颈鳞状细胞癌和HPV（均由NIH资助）的经验基础上。我们进行这些研究的能力来自于利用瑞典独特的先决条件，即计算机化登记册中存在的用于基于人口的PAP涂片筛查的大量文件，所有腺癌事件病例的潜在确定，以及获得存档涂片和组织标本。在这个大型研究基础中使用巢式病例对照设计，完成长达32年的随访，将确定511名腺癌女性和511名单独匹配的对照女性。 使用经验证和敏感的PCR检测，将在每个参与者的所有可用涂片中分析HPV DNA的存在（每个人平均4个涂片，总共约4，088个涂片）。将分析所有入选妇女的HPV持续性，HPV 16/18/45病毒载量和HLA（DQ 6和DR 15型）。宫颈腺癌的致癌HPV感染的相对风险，HPV持续性，HPV 16/18/45高病毒载量，HLA单倍型和这些因素之间的相互作用将估计条件logistic回归。似然比检验将用于区分嵌套模型。为特定目标进行的统计功效计算表明，我们的研究规模足够大。

DESCRIPTION (provided by applicant): The overall objective of this project is to improve the biologic understanding of adenocarcinoma and adenosquamous cancer of the cervix uteri (in the following referred to as adenocarcinoma) through investigation of its viral etiology, and genes encoding certain human leukocyte antigen (HLA) haplotypes. The long-term objective is to propose rational prevention strategies for this disease. Our main specific aims are to: 1) estimate the relative risks for adenocarcinoma both as a function of HPV presence overall and as a function of time since first detected infection with human papillomavirus (HPV); 2) to assess whether persistence and/or a high initial HPV 16/18/45 viral load is a determinant of adenocarcinoma; 3) to assess whether certain HLA haplotypes are associated with risk for adenocarcinoma, and if the association is mediated via a higher viral load and/or persistence of HPV 16/18/45. This project will build on experience from two previous studies examining squamous cell cervical cancer and HPV (both funded by NIH). Our capacity to conduct these studies is derived from the utilization of unique prerequisites in Sweden, namely the extensive documentation present in computerized registers for population-based PAP-smear screening, potential ascertainment of all incident cases of adenocarcinoma, and access to archival smears and tissue specimens. Using a nested case-control design in this large study base, with up to 32 years of complete follow-up, 511 women with adenocarcinoma and 511 individually matched control women will be identified. Using validated and sensitive PCR-assays, the presence of HPV DNA will be analyzed in all available smears from each participant (on an average four smears per individual, giving totally about 4,088 smears).HPV persistence, HPV16/18/45 viral load and HLA (types DQ6 and DR15) will be analyzed for all included women. Relative risks of cervical adenocarcinoma for oncogenic HPV infections, HPV persistence,HPV16/18/45 high viral load, HLA haplotype and interactions between these factors will be estimated with conditional logistic regression. The likelihood ratio test will be used to discriminate between nested models. Statistical power calculations produced for the specific aims show that our study is adequately sized.