HPV, cervical neoplasia, and vaccination

众所周知，HPV是宫颈癌和其他肛门癌和头颈癌的一个子集，包括许多在艾滋病毒感染背景下升高的癌症(例如宫颈癌和肛门癌)。然而，尽管HPV感染很常见，但癌症的发生却很少见。这表明，除了HPV感染之外，辅助因素对宫颈癌的发展也很重要。本项目旨在阐明HPV及其辅助因子在宫颈癌及其前驱疾病的病因中的作用，明确不同组织学形式的宫颈癌的危险因素是否相似或不同，并将所获得的知识应用于新的预防策略。到目前为止，已经进行了几项研究来实现我们的目标，包括美国的一项关于子宫腺癌和鳞癌的多中心病例对照研究，一项对患有HPV引起的低级别宫颈病变的妇女的纵向研究，以及一项关于台湾的HPV和子宫颈癌的队列研究。到目前为止，这些研究的结果表明：1)虽然HPV感染是所有组织学类型宫颈癌发生所必需的，但在癌症中观察到的HPV类型/变异的分布因组织学而异，2)与不同组织类型宫颈癌相关的辅助因素不同，虽然所有组织学形式的宫颈癌与易患HPV感染的性行为变量有关，但子宫腺癌似乎优先与表明激素参与的危险因素有关，3)免疫相关基因(包括HLA和KIR基因)的多态与宫颈癌的发生有关，以及4)HPV DNA检测是预防宫颈癌的有用的筛查试验。此外，我们进行的分子流行病学研究表明，1)自然感染产生的抗体可以预防HPV再次感染，2)粘膜免疫指标在月经周期中变化，并受口服避孕药使用的影响，这表明对局部免疫及其在HPV持续和进展易感性中的作用的研究需要考虑这些变化。这项工作是由校内NCI基金赞助的。

HPV is known to be a necessary cause of cervical cancer and a subset of other anogenital and head and neck cancers, including many cancers (e.g., cervical and anal cancers) that are elevated in the context of HIV. However, while HPV infection is common, development of cancer is rare. This suggests that in additional to HPV infection, co-factors are important for the development of cervical cancer. This project aims to elucidate the role of HPV and co-factors in the etiology of cervical cancer and its precursors, to define whether risk factors are similar or different for different histological forms of cervical cancer, and to apply knowledge gained to novel prevention strategies. Several studies have been conducted to date to achieve our goals, including a multicenter case-control study of cervical adenocarcinomas and squamous cell carcinomas in the US, a longitudinal study of women with low-grade, HPV-induced cervical lesions, and a cohort study of HPV and cervical cancer in Taiwan. Results from these studies to date have shown that 1) while HPV infection is required for the development of all histological types of cervical cancer the distribution of HPV types/variants observed in cancers vary by histology, 2) co-factors associated with distinct histological types of cervical cancer differ and while all histological forms of cervical cancer are associated with sexual behavior variables that predispose to HPV infection, cervical adenocarcinomas appear to be preferentially associated with risk factors that indicate hormonal involvement, 3) polymorphisms in immune-related genes (including HLA and KIR genes) are associated with the development of cervical cancer, and 4) HPV DNA testing is a useful screening test for the prevention of cervical cancer. In addition, we have conducted molecular epidemiology studies that have shown that 1) antibodies generated in response to natural infections protect against re-infection with HPV and 2) markers of mucosal immunity vary across the menstrual cycle and are affected by oral contraceptive use, suggesting that studies of local immunity and its role in predisposition to HPV persistence and progression need to account for these changes. This effort is sponsored by Intramural NCI funds.