Intratypic variation of oncogenic HPV types as a risk factor for cervical neoplas

描述（由申请人提供）：生殖器感染致癌型人乳头瘤病毒（HPV）是浸润性宫颈癌（ICC）及其直接前体宫颈上皮内瘤变3级（CIN 3）发展的关键。然而，HPV感染在健康女性中也很常见，通常是短暂的。目前还不清楚为什么大多数感染会自发消退，以及是什么导致HPV感染最终导致ICC。我们推测，病毒的内部序列变异在确定HPV感染的后果中起着重要作用。对HPV类型的内部变异的研究揭示了迄今为止在所有检查的人群中存在各种自然变异。鉴于HPV 16和HPV 18变异体的可变生物学特性的发现，我们现在计划研究11种非HPV 16/18致癌类型（即，HPV 31、33、35、39、45、51、52、56、58、59和68）与ICC和CIN 3的风险密切相关。迄今为止，这11种类型都没有被仔细研究过。拟议的研究将利用参与ASCUS-LSIL分诊研究的妇女人群的现有宫颈标本和流行病学及临床数据，该研究是NCI申办的多中心临床试验，旨在评估对巴氏涂片可疑或轻度异常妇女进行分诊的策略。我们计划通过对部分病毒基因组进行序列分析来确定11种HPV类型中每一种的变异谱系，并通过群体遗传分析来确定可能受到选择压力的核苷酸变异（目的1）。我们的实验室数据将链接到ALTS数据库。通过分析链接的数据文件，我们将确定一组与CIN 3风险增加相关的变异（目标2），并阐明HPV变异的种族相关分布和消退（目标3）。本补助金申请是对计划公告（PA-07-356）的回应。这项研究将为我们理解HPV变异相关的宫颈肿瘤发病机制提供重要的见解。了解非HPV 16/18致癌类型的细胞内变异对开发针对这些HPV类型的疫苗具有重要价值。认识到HPV变异体的病因作用以及变异体的种族相关分布和持续性可能有助于开发生物标志物，以改善宫颈癌前病变妇女的筛查计划和临床管理，以进行二级预防。公共卫生相关性：生殖器感染致癌性人乳头瘤病毒（HPV）是 宫颈癌的早期症状HPV类型在生物学和病原学上不同。该研究旨在调查11种致癌HPV类型的内部变异的病因学作用。来自拟议研究的数据将通过识别用于开发下一代疫苗的各种天然变体对初级宫颈癌预防工作具有重要意义，并通过开发生物标志物来改善当前的筛查和临床管理计划对二级预防工作具有重要意义。

DESCRIPTION (provided by applicant): Genital infection with oncogenic types of human papillomavirus (HPV) is central to the development of invasive cervical cancer (ICC) and its immediate precursor, cervical intraepithelial neoplasia grades 3 (CIN 3). However, HPV infection is also common in healthy women and usually transient. It is still largely unknown why most of the infections regress spontaneously and what makes HPV infections eventually lead to ICC. We hypothesize that intratypic sequence variations of the virus play an important role in defining consequences of HPV infections. Studies on intratypic variations of HPV types have revealed the presence of a variety of natural variants in all populations examined to date. Given the findings of variable biologic properties of HPV16 and HPV18 variants, we now plan to investigate the etiologic role of intratypic variations of 11 non-HPV16/18 oncogenic types (i.e., HPV31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68) that are strongly associated with risk of ICC and CIN 3. None of these 11 types has been carefully studied so far. The proposed study will utilize the existing cervical specimens and epidemiological and clinical data from the population of women who participated in the ASCUS-LSIL Triage Study, the NCI sponsored multi-center clinical trial designed to evaluate strategies for triaging women with equivocal or mildly abnormal Pap smears. We plan to define lineages of the variants for each of 11 HPV types by performing sequence analyses of the partial viral genome and identify nucleotide alterations that are likely to be under selective pressure by population genetic analyses (Aim 1). Our laboratory data will be linked to the ALTS database. By analyzing the linked data file, we will identify a set of the variants that are associated with an increased risk of CIN 3 (Aim 2) and clarify the race-associated distribution and regression of HPV variants (Aim 3). This grant application is in response to the program announcement (PA-07-356). The proposed study will provide important insights into our understanding of HPV variant-related pathogenesis of cervical neoplasia. Knowledge of the intratypic variations of non-HPV16/18 oncogenic types will be of important value to the development of vaccines against these HPV types. Recognition of the etiologic role of HPV variants and the race-associated distribution and persistence of the variants may help with the development of biomarkers to improve screening programs for and clinical management of women with cervical precancerous lesion for a secondary prevention. PUBLIC HEALTH RELEVANCE: Genital infection with oncogenic human papillomavirus (HPV) is central to the development of cervical cancer. HPV types differ biologically and etiologically. The proposed study was designed to investigate the etiologic role of intratypic variations of 11 oncogenic HPV types. Data from the proposed study will be of importance to primary cervical cancer prevention efforts through identification of various natural variants for development of the next generation of vaccines and to secondary prevention efforts through development of biomarkers for improvement of current programs for screening and clinical management.