Disparities in Cervical Cancer Precursors and Deregulation of Imprinted Genes

摘要 尽管对宫颈上皮内瘤变(CIN)的筛查及其积极治疗降低了宫颈癌的发病率和死亡率，但据估计，美国每年仍有11000例浸润性癌(ICC)和4万例原位癌(CIS)被诊断出来。与白人相比，非裔美国人(AA)的ICC发病率高60%，死亡率高两倍以上。尽管检测前驱病变的筛查率和高危人乳头瘤病毒(HPV)感染的可比性以及吸烟等辅助因素的可比性，但发病率和死亡率仍存在差异。这种差异的原因在很大程度上是未知的，但可能涉及与医疗保健、遗传学和表观遗传学差异有关的两个因素。我们最近得到了资金来评估表观遗传学的程度 在1500名白人、非洲人和西班牙人中，表观遗传不稳定基因座的解除调控可以预测CIN1进展为严重的上皮内瘤变和宫颈癌(CIN2或更严重)(R01CA142983)。平均而言，在25岁以上的女性中，~1/3的CINL进展为CIN2+。而遗传/表观遗传因素与更多 再生障碍性贫血的侵略性表型可能解释了观察到的一些差异，社会和医学因素也可能是重要的决定因素。对于这一应用，我们的中心假设是，社会和医疗因素，包括次优的提供者沟通和获得护理的机会，在很大程度上导致了医疗不足 在少数民族人群中观察到宫颈癌前驱病变的随访，导致诊断的后期。我们将招收多达500例经组织学确诊的CINL病例(我们预计约三分之一的CIN病例将不会遵守预定的预约)，以解决以下具体目标： 目标1：确定与不遵守计划的后续访问有关的因素。我们将对首批20-25名非洲裔美国人、拉丁裔和白人女性进行深入采访，他们在确诊为CIN1后未能遵守预定的6个月随访预约。目标2：根据目标1中确定的因素，制定和 管理一份调查问卷，以确定先前确定的因素，如获得治疗的机会、次优的患者/提供者沟通，以及通过深入访谈确定的其他社会因素与进展到CIN2或更糟的关联程度，以及这种关联是否因种族/民族而异；目的S：开发一种基于理论的干预措施，以增加对预定预约的遵守，预计这些女性中高达50%会坚持随访。 意义重大。在CINL人群中确定与不坚持随访相关的因素，如果不同种族不同，将导致更有针对性的干预措施，以增加依从性，并降低进展为ICC差异的风险。拟议的研究还将减少母公司研究中的自然减员，以及 产生的初步数据将是一项由沃德劳-斯廷森博士领导的更大规模研究的关键。

Abstract Although screening for uterine cervical intraepithelial neoplasia (CIN) and its aggressive treatment has resulted in decreased cervical cancer incidence and mortality, an estimated 11,000 cases of invasive cen/ical cancer (ICC) and 40,000 cases of carcinoma in situ (CIS) continue to be diagnosed every year in the United States. ICC incidence is 60% higher and mortality over two times higher in African Americans (AA) compared to whites. Such disparate rates in incidence and mortality are despite comparable screening rates to detect precursor lesions and comparable prevalence of'high risk' human papillomavirus (HPV) infection and co-factors such as cigarette smoking. Reasons for such disparities are largely unknown but may involve both factors related to differences in medical care, genetics and epigenetics. We have recentiy been funded to evaluate the extent to which epigenetic deregulation of epigenetically labile loci predict progression of CINl to severe intraepithelial neoplasia and cervical cancer (CIN2 or worse) in 1,500 Whites, African and Hispanics (R01 CA142983). On average, ~1/3 of CINl in women aged 25+ years progress to CIN2+. While genetic/epigenetic factors associated with a more aggressive phenotype in AA may explain some ofthe disparities observed, social and medical factors are also likely to be important determinants. For this application, our central hypothesis is that social and medical factors, including suboptimal provider communication and access to care, contribute substantially to inadequate follow-up of cervical cancer precursor lesions, leading to later stage at diagnosis observed in minority populations. We will enroll up to 500 histologically confirmed CINl cases (about one third of CIN cases that we anticipate will not adhere to scheduled appointments) to address the following specific aims: Aim 1: Identify factors associated with poor adherence to scheduled follow-up visits. We will conduct in-depth interviews among the first 20-25 African Americans, Latina and white women who fail to keep scheduled 6-month follow-up appointments, following a CIN1 diagnosis. Aim 2: Based on factors identified in Aim 1, develop and administer a questionnaire to determine the extent to which previously identified factors such as access to care, suboptimal patient/provider communication, and other social factors identified through in-depth interviews are associated with progression to CIN2 or worse and whether this association varies by race/ethnicity; Aim S: Develop a theory-informed intervention to increase adherence to scheduled appointments, anticipating up to 50% of these women adhere to a follow-up visit. Significance. Identifying factors associated with non-adherence to follow-up and if it varies by race, in the CINl population will lead to better focused interventions to increase adherence, and decreases in the risk of progression to ICC disparities. The proposed study will also decrease attrition in the parent study, and preliminary data generated will be essential for a larger study that will be led by Dr. Wordlaw-Stinson.