Molecular epidemiology of cervical adenocarcinoma

描述(申请人提供)：本项目的总体目标是通过研究其病毒病因和编码某些人类白细胞抗原(HLA)单倍型的基因，提高对子宫颈癌和子宫腺鳞癌(以下简称腺癌)的生物学认识。长期目标是为该病提出合理的预防策略。我们的主要目标是：1)估测人类乳头瘤病毒(HPV)感染以来人类乳头瘤病毒(HPV)整体存在和时间的函数对腺癌的相对风险；2)评估持续和/或高初始HPV16/18/45病毒载量是否是腺癌的决定因素；3)评估某些人类白细胞抗原单倍型是否与腺癌的风险相关，以及这种关联是否通过较高的病毒载量和/或HPV16/18/45持续存在而介导。该项目将建立在之前两项研究鳞状细胞癌和HPV(均由NIH资助)的经验基础上。我们进行这些研究的能力源于瑞典独特的先决条件的利用，即在基于人口的PAP涂片筛查的计算机化登记中存在大量文件，可能确定所有腺癌病例，以及获得档案涂片和组织标本。在这个大型研究基地采用嵌套病例对照设计，通过长达32年的完整随访，将确定511名患有腺癌的妇女和511名单独匹配的对照妇女。 使用有效和敏感的聚合酶链式反应分析，将分析每个参与者所有可用的涂片中HPV DNA的存在(平均每个人四次涂片，总共约4,088个涂片)。将对所有纳入的女性进行HPV持久性、HPV16/18/45病毒载量和人类白细胞抗原(DQ6和DR15型)的分析。HPV感染、HPV持续感染、HPV16/18/45高病毒载量、人类白细胞抗原单倍型以及这些因素之间相互作用的相对风险将通过条件Logistic回归进行评估。似然比检验将用于区分嵌套模型。针对特定目标产生的统计功率计算表明，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.