Disparities in Cervical Cancer Precursors and Deregulation of Imprinted Genes

摘要 尽管子宫颈上皮内瘤变（CIN）筛查及其积极治疗已导致宫颈癌发病率和死亡率下降，但在美国每年仍有估计11，000例浸润性宫颈癌（ICC）和40，000例原位癌（CIS）被诊断。ICC的发病率高60%，死亡率在非洲裔美国人（AA）比白人高两倍以上。尽管检测前驱病变的筛查率和“高危”人乳头瘤病毒（HPV）感染和吸烟等辅助因素的患病率相当，但发病率和死亡率却如此不同。这种差异的原因在很大程度上是未知的，但可能涉及两个因素有关的差异，在医疗保健，遗传学和表观遗传学。我们最近得到了资助来评估表观遗传学在多大程度上 表观遗传学不稳定基因座的失调预测了1，500名白人、非洲人和西班牙人中CIN 1向严重上皮内瘤形成和宫颈癌（CIN 2或更差）的进展（R 01 CA 142983）。平均而言，25岁以上女性中约1/3的CIN 1进展为CIN 2+。虽然遗传/表观遗传因素与更多的 AA中的攻击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。对于这个应用程序，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，大大有助于不充分的 对宫颈癌前病变进行随访，导致在少数群体中观察到诊断时的晚期。我们将招募多达500例组织学证实的CIN 1病例（我们预计约三分之一的CIN病例将不遵守预定的预约）以解决以下具体目标： 目的1：确定与计划随访依从性差相关的因素。我们将在第一批20-25名非洲裔美国人、拉丁裔和白色女性中进行深入访谈，这些女性在CIN 1诊断后未能保持预定的6个月随访预约。目标2：根据目标1中确定的因素， 进行问卷调查，以确定先前确定的因素（如获得护理、次优患者/提供者沟通以及通过深入访谈确定的其他社会因素）与进展至CIN 2或更差的相关程度，以及这种相关性是否因种族/民族而异;目的S：制定一个理论知情的干预措施，以增加遵守预定的约会，预计高达50%的这些妇女坚持随访。 意义在CIN 1人群中，识别与不依从随访相关的因素，并且如果其因种族而异，则将导致更好地集中干预以增加依从性，并降低进展为ICC差异的风险。拟议的研究还将减少母研究中的损耗， 初步数据将是必不可少的一个更大的研究，将由博士Wordlaw-Stinson领导。

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.