Prospective study on viral load of cervical cancer

描述（由申请人提供）：我们的长期目标是通过提高对生物学的认识和更具成本效益的筛查策略来预防宫颈癌。虽然人乳头瘤病毒（HPV）感染是宫颈癌的一个既定原因，但尚不完全清楚HPV的病毒载量是否会影响原位癌（CIS）向浸润性癌的进展和/或与遗传因素相互作用。因为临床干预无法直接观察这种进展。需要采取非常规的办法。我们的主要具体目标是：1）量化CIS和浸润性癌症的绝对和相对风险，作为自检测到HPV和HPV 16高病毒载量以来的时间的函数，2）评估持续的HPV 16高病毒载量是否是CIS和浸润性癌症发展的决定因素，3）评估特异性HLA DQ 6/DR 15单倍型是否与CIS和浸润性癌症的风险相关，以及该关联是否通过较高的病毒载量和/或HPV的持久性介导;以及4）评估衣原体感染是否与CIS和浸润性癌症的风险相关。以早期CIS研究（由NCI资助）的经验为基础。我们将利用瑞典的独特先决条件，即在计算机化登记册中记录的广泛的基于人口的子宫颈抹片检查。确定所有CIS和浸润性癌症的发病病例。以及获取涂片和组织样本档案。在这个大型研究基地中使用嵌套设计，进行长达25年的完整随访，我们将确定600名浸润性癌症女性，600名CIS女性和600名单独匹配的对照女性。使用经验证的敏感PCR检测，将在每位参与者的所有可用涂片中分析病毒DNA的存在-以及HPV 16的病毒载量-（平均每人4份，总计约9600份涂片）。将在所有入选女性的首次涂片中分析HLA和沙眼衣原体。将通过条件logistic回归和非参数方法的绝对风险函数估计相对风险和相互作用。

DESCRIPTION (provided by applicant): Our long-term objective is to bring about prevention of cervix cancer through improved biologic understanding and more cost-effective screening strategies. Although human papilloma virus (HPV) infection is an established cause of cervical cancer, it is incompletely known if viral load of HPV influences progression from cancer in situ (CIS) to invasive cancer and/or interacts with genetic factors. Since clinical intervention precludes direct observation of this progression. unconventional approaches are needed. Our main specific aims are to ; 1) quantify the absolute and relative risks for CIS and invasive cancer as a function of time since detected HPV and HPV 16 high viral load, 2) assess whether persistent HPV 16 high viral load is a determinant for development of CIS and invasive cancer, 3) assess whether the specific HLA DQ6/DR15 haplotype is associated with risks for CIS and invasive cancer, and if the association is mediated via a higher viral load and/or persistence of HP V. and 4) assess whether Chlamydia infection is associated with risks for CIS and invasive cancer. Building on experience from an earlier study of CIS (funded by NCI). we will take advantage of unique prerequisites in Sweden created by extensive population-based PAP smear screening documented in computerised registers. ascertainment of all incident cases of CIS and invasive cancer. and access to archival smears and tissue specimens. Using a nested design in this large study base with up to 25 years of complete follow-up, we will identify 600 women with invasive cancer, 600 women with CIS and 600 individually matched control women to each case-group. Using validated and sensitive PCR assays, the presence of viral DNA - and for HPV 16, also the viral load -will be analyzed in all available smears from each participant (on average four per individual, giving a total of about 9600 smears). HLA and C trachomatis will be analyzed in the first smear from all included women. Relative risks and interactions will be estimated by conditional logistic regression and absolute risk functions by non-parametric methods.