Molecular epidemiology of cervical adenocarcinoma

项目描述（由申请人提供）：本项目的总体目标是通过研究子宫颈腺癌和腺鳞癌（以下简称腺癌）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，提高对其生物学的认识。长期目标是针对这种疾病提出合理的预防策略。我们的主要具体目标是：1)估计腺癌的相对风险与HPV总体存在的关系以及与首次检测到人乳头瘤病毒（HPV）感染的时间的关系；2)评估持续和/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，以及这种关联是否通过较高的病毒载量和/或持续存在的HPV 16/18/45介导。该项目将建立在先前两项检查宫颈鳞状细胞癌和HPV的研究（均由NIH资助）的经验基础上。我们开展这些研究的能力来源于瑞典独特的先决条件的利用，即基于人群的pap涂片筛查的计算机登记中存在的大量文件，所有腺癌事件病例的潜在确定，以及获得档案涂片和组织标本。在这个大型研究基础中，使用嵌套病例对照设计，长达32年的完整随访，将确定511名患有腺癌的女性和511名单独匹配的对照女性。

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.