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

致癌 HPV 类型的型内变异是宫颈肿瘤的危险因素

• 批准号: 8193200
• 负责人: LONG FU XI
• 金额: $ 38.61万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193200
• 关键词: Address; Applications Grants; Atypical Squamous Cell; Base Sequence; Biological Markers; Cancer Etiology; Categories; Cervical; Cervical Intraepithelial Neoplasia; Clinical; Clinical Data; Clinical Management; Clinical Trials Design; Code; DNA; DNA Sequence; Data; Data Files; Databases; Detection; Development; Enrollment; Epidemiology; Family; Genes; Genomics; Health; Histologic; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus 31; Human papilloma virus infection; Human papillomavirus 11; Human papillomavirus 16; Human papillomavirus 18; In Vitro; Infection; Knowledge; Laboratories; Lead; Lesion; Link; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Molecular Epidemiology; Multi-Institutional Clinical Trial; NIH Program Announcements; Neoplasms; Nucleotides; Oncogenic; Oncogenic Viruses; Open Reading Frames; Outcome; Pap smear; Pathogenesis; Play; Population; Population Genetics; Premalignant; Property; Proteins; Race; Randomized Clinical Trials; Research; Risk; Risk Factors; Role; Sampling; Screening procedure; Secondary Prevention; Sequence Analysis; Specimen; Squamous intraepithelial lesion; Testing; Therapeutic Intervention; Time; Triage; Vaccines; Variant; Viral; Viral Genome; Viral Oncogene; Virus; Visit; Woman; base; carcinogenesis; cervical cancer prevention; design; driving force; follow-up; genetic analysis; genital infection; high risk; improved; insight; novel vaccines; pressure; programs; prophylactic; response; vaccine development; viral DNA; virus development

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.

描述（由申请人提供）：人类乳头瘤病毒（HPV）的生殖器感染对于浸润性宫颈癌（ICC）及其直接前体，颈椎上皮内肿瘤级别3（CIN 3）至关重要。但是，HPV感染在健康女性中也很常见，通常是短暂的。对于为什么大多数感染会自发回归以及使HPV感染最终导致ICC的原因，这仍然很大程度上尚不清楚。我们假设病毒的内部序列变化在定义HPV感染的后果中起重要作用。 HPV类型内型变化的研究表明，迄今为止所有研究的人群中存在多种自然变异。 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.到目前为止，尚未对这11种类型进行仔细研究。拟议的研究将利用参与ASCUS-LSIL TriaGE研究的女性人群的现有宫颈标本以及流行病学和临床数据，NCI赞助了多中心临床试验，旨在评估旨在评估对妇女的策略，该策略是对妇女进行地位或轻度异常的羊皮smears的策略。我们计划通过进行部分病毒基因组的序列分析来定义11种HPV类型中每种变体的谱系，并确定可能通过人群遗传分析在选择性压力下的核苷酸变化（AIM 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（AIM 2）相关的变体，并阐明与种族相关的HPV变体分布和回归（AIM 3）。该赠款申请是对计划公告（PA-07-356）的回应。拟议的研究将为我们对HPV变异相关的宫颈肿瘤发病机理的理解提供重要的见解。对非HPV16/18致癌类型的内部内部变化的了解对于针对这些HPV类型的疫苗开发具有重要价值。认识HPV变体的病因作用以及与种族相关的变体的分布和持久性可能有助于开发生物标志物，以改善宫颈前癌性病变妇女的筛查计划和临床管理，以进行次要预防。公共卫生相关性：与致癌人乳头瘤病毒（HPV）的生殖器感染是 宫颈癌的发展。 HPV类型在生物学和病因上有所不同。拟议的研究旨在研究11种致癌性HPV类型的内部内部变化的病因作用。拟议研究的数据将对预防原发性宫颈癌的预防工作非常重要，这是通过确定下一代疫苗开发的各种自然变体，以及通过开发生物标志物来改善当前的筛查和临床管理计划，以进行二级预防工作。