HPV AND CERVIX NEOPLASIA--A CASE CONTROL STUDY

描述：（改编自申请人的摘要）：申请人的 目的是增进对生殖器所起作用的了解， 人乳头瘤病毒（HPV）在原位癌（CIS）病因学中的作用--以及 子宫颈的恶性肿瘤。 虽然HPV的因果作用 很可能，没有大规模的基于人群的前瞻性研究已经检查了其 从正常上皮到CIS的自然史中的作用，也不是 细胞介导的免疫（由HLA单倍型确定），微异质性 (or HPV基因组中的突变），或其他可能决定 HPV感染的短暂性/持续性。 也没有所谓的有序 宫颈瘤变的进展或单克隆起源已经确立。 他们 提出一个广泛的，跨学科的病例对照研究，嵌套在 基于人口的队列。 这项研究利用瑞典独特的机会， 严格研究定义、长期随访和涂片检索 和组织病理学标本;它具有广泛的形态学和分子生物学特征。 成分 主要的具体问题涉及：1）进展的决定因素： HPV感染的长期模式（一过性、持续性、再感染） 型，涂片和CIS病变中HPV的一致性，微观异质性 或HPV基因组中的获得性突变， 单倍型和/或吸烟; 2）进展和克隆性： HPV和形态学以及伴随的单克隆或多克隆性 X染色体失活所指示的病变。 他们将跟踪调查一组以人口为基础的妇女， 1969年后的第一次子宫颈抹片检查正常。 至少400例CIS事件 将纳入400名匹配的对照， 采访 每个受试者平均进行5次连续涂片（总计 约4，000个涂片）将进行DNA提取和基于PCR的分析 包括19种HPV类型和HLA-DQB 1单倍型的分型 和HLA-DRB 1）。 此外，在选定的集中（关于 100例）将进行HPV基因组部分测序， 研究微观异质性。 进展和克隆性的详细研究 将进行;标本约50例CIS与多个 将对离散的病变进行显微解剖，然后进行DNA提取， 分析HPV以及X染色体失活。 这些数据将 用于许多不同的分析，包括条件Logistic 回归分析

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.