HPV AND CERVIX NEOPLASIA--A CASE CONTROL STUDY

描述：(摘自申请人摘要)：申请人的 目的是促进对生殖器所起作用的理解 人乳头瘤病毒(HPV)在原位癌(CIS)病因中的作用 推论浸润性癌症--子宫颈癌。而人乳头瘤病毒的因果作用 很可能，没有一项大规模的基于人群的前瞻性研究检查过它的 在从正常上皮到独联体的自然历史中的作用，也不是作用 细胞免疫(由人类白细胞抗原单倍型决定)，微异质性 HPV基因组的(或突变)，或其他可能决定 HPV感染的暂时性/持久性。所谓的秩序也不是 宫颈肿瘤的进展或单克隆性起源已被证实。他们 提出一项广泛的、跨学科的病例对照研究，嵌套在 以人口为基础的队列。这项研究使用了独特的瑞典机会 严格的研究基础定义、长期随访和涂片检索 和组织病理学标本；它有广泛的形态和分子 组件。 主要的具体问题与1)进程的决定因素有关： HPV感染的长期模式(暂时性、持续性、再感染性) 类型、涂片中HPV与CIS病变的一致性、微观异质性 或HPV基因组中的获得性突变，影响人类白细胞抗原的修饰 单倍型和/或吸烟；2)进展和克隆：之间的相关性 人乳头瘤病毒及其伴发的单克隆性或多克隆性 X染色体失活所示的损伤。 他们将在1993年对一群以人口为基础的妇女进行跟踪调查，这些妇女 1969年以后的第一次巴氏涂片是正常的。至少400起独联体事件 将包括400个匹配的对照，并接受电话 面试。每名受试者平均五次顺序涂片(总计 约4,000份涂片)将进行DNA提取和基于PCR的分析 包括19种HPV分型，以及人类白细胞抗原II类单倍型(人类白细胞抗原DQB1 和人类白细胞抗原-DRB1)。此外，在选定的集合中(关于 100例)对部分HPV基因组进行测序，以 研究微观异质性。关于级数和克隆的详细研究 将进行；约50例多发性多发性口腔炎患者的标本 将对离散的病变进行显微解剖，然后提取DNA和 人乳头瘤病毒及X染色体失活分析。这些数据将是 用于许多不同的分析，包括条件逻辑分析 回归。

DESCRIPTION: (Adpated from the Applicant's Abstract): The applicants' objective is to advance the understanding of the role played by genital human papillomavirus (HPV) in the etiology of carcinoma in situ (CIS) -- and inferentially invasive cancer -- of the cervix. While a causal role of HPV is likely, no large population-based, prospective study has examined its role in the natural history from normal epithelium to CIS, nor the role of cell-mediated immunity (as determined by HLA haplotype), microheterogeneity (or mutations) in the HPV genome, or of other factors that may determine transience/persistence of HPV infection. Nor has the purported orderly progression or monoclonal origin of cervix neoplasia been established. They propose a broad, interdisciplinary case-control study, nested in a population-based cohort. This study uses unique Swedish opportunities for a stringent study base definition, long-term follow-up and retrieval of smears and histopathologic specimens; it has an extensive morphologic and molecular component. The main specific questions relate to 1) determinants of progression: long-term pattern of infection (transience, persistence, reinfection) by HPV type, concordance between HPV in smears and CIS lesions, microheterogeneity or acquired mutations in the HPV genome, effect modification by HLA haplotype and/or smoking; 2) progression and clonality: correlation between HPV and the morphology as well as mono- or polyclonality of concomitant lesions as indicated by x-chromosome inactivation. They will follow up through 1993 a population-based cohort of women whose first PAP smear after 1969 was normal. At least 400 incident cases of CIS and 400 matched controls will be included and subjected to a telephone interview. On average five sequential smears from each subject (a total of about 4,000 smears) will undergo DNA extraction and PCR-based analyses including typing of 19 HPV-types, and of HLA class II haplotypes (HLA-DQB1 and HLA-DRB1) in one smear per individual. Also, in a selected set (about 100 cases) sequencing of a proportion of the HPV genome will be performed to study microheterogeneity. Detailed studies of progression and clonality will be carried out; the specimens from about 50 cases of CIS with multiple discrete lesions will be microdissected, followed by DNA extraction and analysis of HPV as well as X-chromosome inactivation. These data will be used on a number of different analyses including conditional logistic regression.