Methylation and Related Anogenital HPV Cancers

甲基化和相关的肛门生殖器 HPV 癌症

• 批准号: 7231117
• 负责人: DOROTHY J. WILEY
• 金额: $ 15.08万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7231117
• 关键词: Algorithms; Anal Intraepithelial Neoplasia; Anus; Biological Markers; Biological Process; Bisexual; Caring; Cell physiology; Cells; Cervix Uteri; Cessation of life; Characteristics; Chronic; Clinical; Clinical Data; Consensus; Cytosine; DNA; Data; Diagnostic; Disease; Disease Progression; Dysplasia; Enhancers; Environmental Risk Factor; Enzymes; Epidemiologic Methods; Epigenetic Process; Event; Gays; Genetic Transcription; Genome; HIV; HPV-High Risk; Health; Homosexuals; Human; Human Papillomavirus; Human papilloma virus 31; Human papilloma virus infection; Human papillomavirus 16; Individual; Infection; Invasive; Investigation; Lesion; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Medical Surveillance; Methylation; Molecular Biology Techniques; Morbidity - disease rate; Neoplasms; Numbers; Pattern; Play; Population; Premalignant; Prevalence; Public Health; Recording of previous events; Risk; Role; Sampling; Screening procedure; Standards of Weights and Measures; Testing; Time; Treatment outcome; Viral Genome; Viral load measurement; Virus Diseases; Visit; burden of illness; cohort; disease natural history; improved; latent infection; men; men who have sex with men; men' s group; mortality; prevent; promoter; tool; transcription factor; transgender

DESCRIPTION (provided by applicant): Anal cancer is an emerging health crisis for homosexual men, especially within the context of human immunodeficiency virus (HIV) infection. Like invasive cervical cancer, intra-anal cancers are largely attributable to chronic, high-risk human papillomavirus (HPV) infections. These infections and their associated low- and high-grade anal intraepithelial neoplasias (AIM) are common for men with a history of receptive anal intercourse. Though the prevalence of anal dysplasia is high, malignancy is a relatively rare occurrence. Domestically, there is no consensus for standards of care, and the outcome of treatment algorithms is largely unsatisfactory. There is an urgent need to identify key events in the underlying natural history of disease, which will enable clinicians to determine which individuals need immediate treatment or can remain under careful surveillance. More sensitive biomarkers that can discriminate between men likely to progress from those that do not will allow better clinical algorithms to be tested. In the long term, these strategies will reduce morbidity and mortality and diminish the population's burden of disease. Methylation is an adaptive cellular process that hinders transcription of foreign DNA by making viral genomes less accessible to host-cell transcription factors and enzymes. Our recent studies suggest methylation of HPV genomes may be an epigenetic determinant, responsible for promoting latent infection and clinical disease progression. This investigation focuses on two aims using epidemiological methods and molecular biology techniques. First, we will determine whether previously observed relationships between methylation of HPV16 genomes and disease state are observable in 91 HIV/HPV16 co-infected men that have been evaluated for AIM. Second, using longitudinally-collected clinical samples and controlling for the effect of time-dependent covariates, we will determine whether particular baseline patterns of methylation in HPV16 genomes predict methylation patterns overtime in three high-risk HPVs. PUBLIC HEALTH STATEMENT: The findings from this study will improve the public's health by improving anal cancer screening accuracy through the identification of reliable biomarkers, to ultimately prevent premature death.

描述（由申请人提供）：肛门癌是同性恋男性的一种新出现的健康危机，特别是在人类免疫缺陷病毒（HIV）感染的背景下。与浸润性宫颈癌一样，肛门内癌主要归因于慢性高危人乳头瘤病毒（HPV）感染。这些感染及其相关的低度和高度肛门上皮内瘤变（AIM）在有接受性肛交史的男性中很常见。虽然肛门发育不良的患病率很高，恶性肿瘤是一个相对罕见的发生。在国内，对护理标准没有共识，治疗算法的结果基本上不令人满意。目前迫切需要确定疾病基本自然史中的关键事件，这将使临床医生能够确定哪些人需要立即治疗或可以继续接受仔细监测。更敏感的生物标志物可以区分可能进展的男性和不可能进展的男性，这将允许测试更好的临床算法。从长远来看，这些战略将降低发病率和死亡率，减轻人口的疾病负担。甲基化是一种适应性细胞过程，通过使宿主细胞转录因子和酶不易接近病毒基因组来阻碍外源DNA的转录。我们最近的研究表明HPV基因组甲基化可能是一个表观遗传决定因素，负责促进潜伏感染和临床疾病进展。本研究主要采用流行病学方法和分子生物学技术。首先，我们将确定先前观察到的HPV 16基因组甲基化与疾病状态之间的关系是否在91名已进行AIM评估的HIV/HPV 16共感染男性中可观察到。第二，使用连续收集的临床样本并控制时间依赖性协变量的影响，我们将确定HPV 16基因组中特定的基线甲基化模式是否预测三种高危HPV中随时间推移的甲基化模式。公共卫生声明：这项研究的结果将通过识别可靠的生物标志物来提高肛门癌筛查的准确性，从而改善公众的健康，最终防止过早死亡。