EPIDEMIOLOGY OF HPV16/18 VARIANTS IN CERVICAL NEOPLASIA

描述（改编自申请人摘要）：人乳头瘤病毒（HPV） 被分为“类型”、“亚型”和变体。“HPV 16和18是 已知是大多数浸润性宫颈癌（ICC）发病机制的核心 以及它们的前驱病变，宫颈上皮内瘤变（CIN）2-3级。 然而，许多妇女获得和自发解决宫颈感染， 这些HPV类型。我们假设某些HPV 16和18变异体在 他们的生物学行为和宫颈肿瘤的风险。一些小 研究已经检查了HPV 16和18变异体与 宫颈肿瘤和许多但不是全部，表明生物学差异， 行为。这些研究结果在大范围内得到证实，更具代表性 人口至关重要。我们建议有效地审查这些问题， 对在所述测定期间收集的样品的子集进行另外的测定， 正在进行的NCI申办的多中心随机临床试验：ASCUS/LSIL 分类研究（ALTS）。这项研究，其中包括5,086名妇女从四个不同的 目前，该委员会正在研究如何最好地管理 意义不明的非典型鳞状细胞的细胞学诊断 （ASCUS）或宫颈的低度鳞状上皮内病变（LSIL）。 ALTS数据集非常丰富，包含标准化收集的结果 和临床标本的检测，详细的问卷调查， 潜在混杂因素，以及组织学和阴道镜诊断， 专家小组审查。通过仅纳入参加研究的妇女的数据， 立即阴道镜臂ALTS，我们将制定精确的估计， HPV 16和IS变异与宫颈瘤变之间的关联（目的1和 2），并确定与CIN 2-3相关的那些变体是否具有 LCR和E6区的DNA水平升高或特定核苷酸变化 基因组（目标4）。此外，利用参加妇女教育方案的妇女的数据， 立即阴道镜检查和保守管理武器，我们将提供 关于HPV 1 6变异体与以下风险之间关系的首次观察： CIN 2-3治疗后复发（目的3）。为了实现这些目标，我们将 对7，290个样本进行基于PCR的检测和分型， (by DNA测序）感染HPV的女性样本中存在的HPV变体 HPV 16（n=548）或18（n=222），并定量（通过基于PCR的动态热循环 检测）1，915例HPV 16阳性和222例 HPV 18阳性样本。这项拟议中的研究可能会使重要的 有助于我们理解HPV 16和18变异体在 宫颈癌的发病机制。

DESCRIPTION (Adapted from applicant's abstract): Human papillomaviruses (HPVs) are classified into "types," "subtypes," and variants." HPV16 and 18 are types known to be central to the pathogenesis of most invasive cervical cancers (ICC) and their precursor lesion, cervical intraepithelial neoplasia (CIN) grade 2-3. However, many women acquire and spontaneously resolve cervical infections with these HPV types. We hypothesize that certain HPV 1 6 and 18 variants differ in their biologic behavior and risk of cervical neoplasia. A number of small studies have examined associations between HPV 1 6 and 18 variants and risk of cervical neoplasia and many, but not all, suggest differences in biologic behaviors. Confirmation of these findings in large, more representative populations is essential. We propose to efficiently examine these issues by performing additional assays on a subset of samples collected during the ongoing NCI-sponsored, multi-center randomized clinical trial: ASCUS/LSIL Triage Study (ALTS). This study, which includes 5,086 women from four different regions of the country, is examining how to best manage women referred with a cytologic diagnosis of atypical squamous cells of uncertain significance (ASCUS) or low- grade squamous intraepithelial lesions (LSIL) of the cervix. The ALTS dataset is extremely rich with results from standardized collection and testing of clinical specimens, detailed questionnaires with information on potential confounders, and histologic and colposcopic diagnoses provided by expert panel review. By including data from only those women enrolled in the immediate colposcopy arm of ALTS, we will develop precise estimates of the association between HPV 1 6 and IS variants and cervical neoplasia (aims 1 and 2), and determine whether those variants that are associated with CIN 2-3 have increased DNA levels or specific nucleotide changes in the LCR and E6 regions of the genome (aim 4). Furthermore, using data from women enrolled in the immediate colposcopy and conservative management arms, we will provide the first observations on the relationship between HPV 1 6 variants and risk for recurrence after treatment for CIN 2-3 (aim 3). To address these aims, we will perform PCR-based assays for detection and typing of 7,290 samples, classify (by DNA sequencing) HPV variants present in samples from women infected with HPV16 (n=548) or 18 (n=222), and quantify (by a PCR-based kinetic thermocycling assay) the amount of HPV DNA present in the 1,915 HPV16-positive and 222 HPV18-positive samples. The proposed study is likely to make important contributions to our understanding of the role of HPV 16 and 18 variants in the pathogenesis of cervical cancer.