Epigenetic changes predict disease course of HPV-related lesions in women 16-24

本研究解决了ARRA目标“05-CA-102* 癌症筛查的比较有效性研究”。拟定的研究目标是开发一种方法来预测CIN 2，3的自然病程，这有助于ARRA的公共卫生目标。在过去的30年里，宫颈癌（ICC） 控制的基础是筛查和治疗所有患有CIN 2、3和CIN 3/CIS的妇女，这些疾病被认为是ICC的前体。立即治疗所有CIN 2，3病变（通过物理破坏）是护理标准，尽管事实上如果不治疗，只有一部分此类病变会进展为ICC，而且在青少年/年轻女性中，许多CIN 2，3病变会自发消退。这种“过度治疗”已经被接受，首先，因为没有办法预测哪些CIN 2，3病变将消退，持续或进展。（目前可用的生物标志物缺乏预测此类病变自然史的必要特异性）。此外，没有其他好的替代医学治疗方法。此外，认为CIN 2、3和CIN 3/CIS的手术和/或消融性切除没有不良后果。然而，最近的研究报告显示， 切除方法（包括最常用的手术：LEEP）与产科发病率增加有关。一些研究还表明，这也适用于消融治疗[Wright TC，2006年宫颈上皮内瘤变或原位腺癌女性管理共识指南]。因此，最近修订了国家管理指南，允许对患有CIN 2，3的青少年和年轻女性进行“长达24个月的观察或治疗”。这种方法给我们的医疗保健系统带来了沉重的负担，因为在美国每年估计有20万名女性青少年/年轻女性被诊断患有CIN 2，3。这些妇女中的许多人现在需要跟踪和密切的临床随访。此外，生长性病变的延迟治疗可能导致需要更深/更宽的切除。为了开始在未来两年解决这一重要问题，我们将：目标一：通过定位ICC、CIS和正常宫颈组织中存在的DAPK 1、IGSF 4、PAX 1、TIMP 3和TFPI 2的甲基化和组蛋白标记，确定对ICC发展至关重要的特异性启动子区域CpG和染色质修饰;目标二：招募100名16-25岁的活检证实为CIN 2-3的女性，并在其活检中和同一天确定Aim 1中鉴定的启动子区域CpG和染色质修饰的状态 脱落细胞样本目标3：每6个月（最长18个月）通过阴道镜检查和脱落细胞样本采集对入选女性进行随访，以进行细胞学和检测，以确定甲基化状态和/或与TWIST 1、DAPK 1、IGSF 4、PAX 1、TIMP 3和TFPI 2相关的染色质标记模式是否随时间发生变化，以及这些变化是否与阴道镜检查和细胞学变化相关。

This study addresses the ARRA goal "05-CA-102* Comparative Effectiveness Research on Cancer Screening". The proposed study goal of developing a method to predict the natural history of CIN 2,3 contributes to the ARRA public health goals in the following way. Over the last 30 years, cervical cancer (ICC) control has been based on screening for, and treating of, all women with CIN 2,3 and CIN 3/CIS, the presumed precursors of ICC. Immediate treatment of all CIN 2,3 lesions (by physical destruction), is the standard of care, despite the fact that only a subset of such lesions ever progress to ICC if left untreated, and further, that in adolescents/young women, many CIN 2,3 lesions spontaneously regress. Such "over treatment" has been accepted, first, as there is no way to predict which CIN 2,3 lesions will regress, persist or progress. (Currently available biomarkers lack necessary specificity for predicting the natural history of such lesions). Further, there are no good alternative medical treatments available. In addition, it was believed that surgical and/or ablative removal of CIN 2,3 and CIN 3/CIS was without untoward consequences. However, recent studies report all excisional approaches (including the most commonly used procedure: LEEP) to be associated with increased obstetrical morbidity. Some studies also suggest that this is also true for ablative therapies [Wright TC, 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ]. National management guidelines were therefore recently revised to allow "either observation for up to 24 months or treatment" for adolescents and young females with CIN 2,3. This approach puts a heavy burden on our health care system as there are an estimated 200,000 female adolescents/young women diagnosed with CIN2,3 in the US each year. Many of these women will now need tracking and close clinical follow up. Further, delayed treatment of growing lesions might lead to the need for deeper/wider excisions for removal. To begin to address this important issue over the next two years, we will: Aim one: define specific promoter region CpGs and chromatin modifications central to development of ICC by mapping methylation and histone marks of DAPK1, IGSF4, PAX1, TIMP3 and TFPI2 present in stored biopsies of ICC, CIS and normal cervical tissues; Aim two: enroll 100 16-25 year old women with biopsy confirmed CIN 2-3 and define the status of the promoter region CpGs and chromatin modifications identified in Aim 1 in their biopsies and same day exfoliated cell samples. Aim 3: Follow enrolled women every 6 months (for up to 18 months) by colposcopy and collection of exfoliated cell samples for cytology and testing to determine whether changes in methylation status and/or the pattern of chromatin marks associated with TWIST1, DAPK1, IGSF4, PAX1, TIMP3 and TFPI2 occur over time, and further, whether such changes are associated with colposcopic and cytologic changes.