Methylation and Related Anogenital HPV Cancers

描述（由申请人提供）：肛门癌是男同性恋者的一种新兴健康危机，特别是在人类免疫缺陷病毒（HIV）感染的背景下。与侵袭性子宫颈癌一样，肛门内癌主要是由慢性、高风险的人乳头瘤病毒（HPV）感染所致。这些感染及其相关的低级别和高级别肛门上皮内瘤变（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，治疗算法的结果在很大程度上令人不满意。迫切需要确定疾病潜在自然史中的关键事件，这将使临床医生能够确定哪些个体需要立即治疗或可以继续密切监测。更敏感的生物标志物可以区分那些可能进展的男性和那些不会进展的男性，这将使更好的临床算法得到测试。从长远来看，这些战略将降低发病率和死亡率，减少人口的疾病负担。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难以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基因组的甲基化可能是一种表观遗传决定因素，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HPV16基因组甲基化与疾病状态之间的关系是否在91名HIV/HPV16合并感染的男性中观察到，这些男性已经进行了AIM评估。其次，使用纵向收集的临床样本并控制时间相关协变量的影响，我们将确定HPV16基因组的特定基线甲基化模式是否预测三种高危hpv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，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。

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.