Disparities in cervical cancer precursors and deregulation of imprinted genes

描述(申请人提供)：尽管对宫颈上皮内病变(CIN)的筛查及其积极治疗降低了宫颈癌的发病率和死亡率，但在美国，估计每年仍有11,000例浸润性宫颈癌(ICC)和40,000例原位癌(CIS)被诊断出来。与白人相比，非裔美国人的ICC发病率高出60%，死亡率高出两倍多。尽管有类似的筛查率来检测前驱病变，可比较的高危人乳头瘤病毒(HPV)感染的流行率，病因，以及吸烟等辅助因素，但发病率和死亡率却如此不同。造成这种差异的原因在很大程度上是未知的。更详细地了解病变的病因，这一进展将改善风险分层，以区分进展风险较低的妇女和那些可能迅速进展为浸润性癌症的妇女。我们假设，基因组印迹基因(一组大约50个已知的生长调节基因，通常只有一个等位基因活跃)的去调控可能会预测宫颈癌的进展。我们发现，与正常宫颈上皮相比，大量印迹基因在ICC中的表达发生了变化。此外，对控制IGF2表达的两个调控区的甲基化分析显示，在CIN2-CIN3分类的标本中偏离正常，在浸润性癌中偏离更严重。综上所述，这些发现表明印记基因在ICC中被解除了调控，这些特征可能会提高对可能进展的CIN病例的检测。我们的中心假设是，印记基因印记调控元件的放松管制，可能受到环境暴露的影响，增加了感染高危HPV的女性患宫颈癌的风险。我们已经展示了环境暴露对印记放松管制的影响的种族差异，因此，进一步假设非裔美国人和拉美裔美国人的风险较高是由于种族/民族差异放松这些基因的影响。我们的具体目标是：(1)确定已知印记基因印记调控元件的解除管制是否与CIN1向CIN2+进展的风险增加相关，以及这种关联是否因种族/民族而异；(2)确定宫颈细胞中印迹调节元件的异常甲基化是否类似于在外周血细胞中发现的甲基化，提示早期事件；并与(I)转录表达，以及(Ii)印迹丢失相关；(3)评估宫颈细胞中已知印迹基因的解除管制是否可用于在500例意义不确定的非典型鳞状细胞(ASCUS)中区分CIN2+女性。为了达到这些目标，我们将招募和跟踪1500名患有CIN1的女性和500名患有ASCUS的女性，并检查12个基因印迹调控元件上的异常甲基化标记与CIN1向CIN2+进展的关系。然后，我们将测试这些标记的性能，以从500例ASCUS病例中识别CIN2+病例。这项拟议研究的数据将改善分诊决策，减少ICC发病率和死亡率的差异。 公共卫生相关性：虽然筛查宫颈上皮内病变以预防宫颈癌导致癌症发病率和死亡率下降，但在美国，估计每年仍有11,000例浸润性宫颈癌和40,000例原位癌被诊断出来，非洲裔美国人的发病率比白人高60%，死亡率是白人的两倍。我们将招募和跟踪1,500例CIN1和500例不确定意义的非典型鳞状细胞(ASCUS)，检查12个基因印迹调控元件异常甲基化与进展到CIN2或更糟之间的关联，然后测试这些标记在ASCUS病例中的表现，而不考虑已知的辅助因素。这项研究的数据将阐明表观遗传去调控在CIN2+中的作用，并为分诊决策提供信息，减少宫颈癌发病率和死亡率的差异。

DESCRIPTION (provided by applicant): Although screening for uterine cervical intraepithelial lesions (CIN) and its aggressive treatment has resulted in decreased cervical cancer incidence and mortality, an estimated 11,000 cases of invasive cervical 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 compared to whites. Such disparate rates in incidence and mortality are despite comparable screening rates to detect precursor lesions, comparable prevalence of 'high risk' human papillomavirus (HPV) infection, the etiologic agent, and co-factors such as cigarette smoking. Reasons for such disparities are largely unknown. A more detailed understanding of the etiology of lesions that progress will improve risk stratification to distinguish women with a low risk of progression from those likely to rapidly progress to invasive cancer. We posit that deregulation of genomically imprinted genes, a group of approximately 50 known growth-regulatory genes where only one allele is normally active, may predict progression to cervical cancer. We found that a substantial group of imprinted genes exhibit altered expression in ICC versus normal cervical epithelium. In addition, methylation analysis of two regulatory regions controlling IGF2 expression shows deviation from normal in specimens with CIN2-CIN3 classification and more profound deviation in invasive cancers. Together, these findings suggest that imprinted genes are deregulated in ICC and these features may improve detection of CIN cases likely to progress. Our central hypothesis is that deregulation at imprint regulatory elements of imprinted genes, likely influenced by environmental exposures, increases risk of progression to cervical cancer in women infected with 'high risk' HPV. We have already shown racial variation on the effect of environmental exposures on imprint deregulation, and thus, further hypothesize that higher risk in African Americans and Hispanics is due to race/ethnic differences in deregulation of these genes. Our specific aims are to: (1) determine if deregulation of imprint regulatory elements of known imprinted genes is associated with increased risk of progression of CIN1 to CIN2+, and whether this association varies by race/ethnicity; (2) determine whether aberrant methylation of imprint regulatory elements in cervical cells is similar to that found in peripheral blood cells, suggesting an early event; and associated with (i) transcriptional expression, and (ii) loss of imprinting; (3) evaluate whether deregulation of known imprinted genes in cervical cells can be used to discriminate women with CIN2+ among 500 Atypical Squamous Cells of Uncertain Significance (ASCUS) cases. To address the Aims, we will recruit and follow 1,500 women with CIN1 and 500 with ASCUS, and examine the association between aberrant methylation markers at imprinted regulatory elements of 12 genes and progression from CIN1 to CIN2+. We will then test the performance of these markers to identify CIN2+ cases from among 500 ASCUS cases. Data from the proposed study will improve triage decisions and reduce disparities in ICC morbidity and mortality. PUBLIC HEALTH RELEVANCE: Although screening for cervical intraepithelial lesions to prevent cervical cancer has resulted in decreased cancer incidence and mortality, an estimated 11,000 cases of invasive cervical cancer and 40,000 carcinomas in situ cases continue to be diagnosed every year in the United States with incidence 60% higher and mortality >2-times higher in African Americans compared to whites. We will recruit and follow 1,500 CIN1 and 500 cases of Atypical Squamous Cells of Uncertain Significance (ASCUS), and examine the association between aberrant methylation at imprinted regulatory elements of 12 genes and progression to CIN2 or worse and then test the performance of these markers in ASCUS cases, independent of known co-factors. Data from this study will elucidate the role of epigenetic deregulation in CIN2+ and inform triage decisions, reducing disparities in cervical cancer incidence and mortality.