EPIDEMIOLOGY OF HPV16/18 VARIANTS IN CERVICAL NEOPLASIA

描述(摘自申请人摘要)：人乳头瘤病毒(HPV) HPV16和HPV18是三种类型 已知是大多数浸润性宫颈癌(ICC)发病机制的核心 其前驱病变为宫颈上皮内瘤变(CIN)2~3级。 然而，许多妇女感染了宫颈感染，并自发地通过 这些人乳头瘤病毒类型。我们假设某些HPV16和18型变种在 他们的生物学行为和宫颈肿瘤的风险。一些小规模的 研究检查了HPV16和18型变异体与罹患 宫颈肿瘤和许多(但不是全部)提示生物学上的差异。 行为。对这些发现的确认在更大范围内更具代表性 人口是必不可少的。我们建议通过以下方式有效地研究这些问题 对在此期间收集的样本的子集执行额外的分析 正在进行的由NCI赞助的多中心随机临床试验：ASCUS/LSIL 分类研究(ALTS)。这项研究包括来自四个不同国家的5086名女性 正在研究如何最好地管理被转介给 意义不明的不典型鳞状细胞的细胞学诊断 宫颈鳞状上皮内病变(ASCUS)或低度鳞状上皮内病变(LSIL)。 ALTS数据集包含非常丰富的标准化采集结果 和对临床样本的测试，详细的问卷调查 潜在的混杂因素，以及组织学和镜诊断 专家小组审查。通过只包括那些登记在 立即进行阴道镜检查，我们将制定准确的估计 HPV16和IS变异与宫颈肿瘤的关系(AIMS 1和 2)，并确定那些与CIN 2-3相关的变异体是否具有 LCR和E6区DNA水平升高或特异性核苷酸变化 基因组(目标4)。此外，使用参加该计划的女性的数据 立即进行阴道镜检查和保守治疗，我们将提供 人乳头瘤病毒16型变异与发病风险关系的初步观察 CIN 2-3治疗后复发(目标3)。为了达到这些目标，我们将 对7290个样本进行基于聚合酶链式反应的检测和分型，对 (通过DNA测序)感染HPV的女性样本中存在HPV变异 HPV16(n=548)或18(n=222)，并定量(通过基于聚合酶链式反应的动力学热循环 化验)1,915例HPV16阳性和222例HPV16阳性患者中HPVDNA的含量 HPV18阳性标本。这项拟议的研究可能会使 有助于我们理解HPV16和18型变异体在人类免疫缺陷病毒感染中的作用 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.