Chlamydia & Aberrant DNA Methylation in Cervical Cancer

描述（由申请方提供）：致癌性人乳头瘤病毒（HPV）感染是ICC发展的必要条件，但不是充分条件，并且需要暴露于其他共致癌物才能进展为恶性肿瘤。在调整致癌HPV的存在后，多项研究报告C。沙眼是一种非致癌的专性细胞内病原体，是ICC的危险因素。我们假设C.沙眼感染由于诱导多种基因的启动子区域中的异常DNA甲基化而增加恶性肿瘤的风险，包括与ICC的发病机制相关的一些基因。DNA甲基化异常是一种与基因转录异常沉默或激活相关的表观遗传学变化，在癌症（包括ICC）的发病机制中被广泛认为是重要的，我们以前已经鉴定了30个高甲基化的ICC相关基因。支持我们假设的证据包括：1）C.沙眼导致慢性炎症延长，产生高水平的活性氧，已知会破坏DNA并改变细胞甲基化。2)C.沙眼是一种专性细胞内病原体，可造成持续感染。体外研究表明，即使在没有整合的情况下，细胞内病原体也会改变细胞甲基化的模式。3)本文综述了近年来国内外有关C.沙眼衣原体感染揭示了我们已经发现的与ICC相关的30个异常甲基化的基因中的相当数量由于C.沙眼感染[初步研究]。确定C.由于沙眼通过诱导异常的DNA甲基化而导致ICC的发病，我们建议在西非进行一项研究，在那里宫颈癌是并且可能仍然是一个主要的公共卫生问题。我们假设我们的30个ICC相关的高甲基化基因的一个子集将与C.有和没有ICC的妇女的沙眼感染。在HPV 16 E6/E7永生化宫颈外细胞中进行的补充体外研究将提供对这种变化的分子基础和自然史的深入了解。这项研究将提供关于感染，炎症和癌症之间已建立但尚未充分理解的相关性的信息，并且可能支持基于改变异常甲基化模式的新治疗方法的开发，这在一期试验中似乎很有希望。

DESCRIPTION (provided by applicant): Infection with oncogenic human papillomaviruses (HPV) is necessary, but not sufficient, for development of ICC and exposure to other co-carcinogens is required for progression to malignancy. After adjusting for the presence of oncogenic HPV, multiple studies report C. trachomatis, a non-oncogenic, obligate intracellular pathogen is a risk factor for ICC. We hypothesize that C. trachomatis infection increases risk of malignancy as a result of inducing aberrant DNA methylation in the promoter region of a variety of genes, including some relevant to the pathogenesis of ICC. Aberrant DNA methylation, widely accepted as important in the pathogenesis of cancers, including ICC, is an epigenetic change associated with the abnormal silencing or activation of gene transcription, and we have previously identified 30 hypermethylated ICC associated genes. Support for our hypothesis includes: 1) C. trachomatis elicits prolonged chronic inflammation which produces high levels of reactive oxygen species, known to damage DNA and alter cellular methylation. 2) C. trachomatis is an obligate intracellular pathogen, which can establish persistent infection. In vitro studies have shown that, even in the absence of integration, intracellular pathogens alter patterns of cellular methylation. 3) A review of our recent in-vitro studies describing alterations of cellular gene transcription associated with C. trachomatis infection revealed that a substantial number of the 30 genes we have shown are aberrantly methylated in association with ICC were down regulated as a result of C. trachomatis infection [Preliminary Studies]. To determine whether C. trachomatis contributes to the pathogenesis of ICC by inducing aberrant DNA methylation, we are proposing a study based in West Africa, where cervical cancer is, and is likely to remain, a major public health problem. We hypothesize that a subset of our 30 ICC-associated hypermethylated genes will be associated with serologic evidence of C. trachomatis infection among women with, and without, ICC. Complementary in vitro studies in HPV 16 E6/E7 immortalized ectocervical cells will provide insights into the molecular basis and natural history of such changes. This study will provide information about the well established, but not well understood association between infection, inflammation, and cancer, and, may support the development of novel treatment approaches based on alteration of aberrant patterns of methylation, which in phase one trials appear promising.