Disparities in cervical cancer precursors and deregulation of imprinted genes

描述（由申请人提供）：尽管子宫颈上皮内病变（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）继续被诊断。非裔美国人的ICC发病率比白人高60%，死亡率高两倍以上。尽管检测前驱病变的筛查率相当，“高危”人乳头瘤病毒（HPV）感染、病原体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。造成这种差异的原因在很大程度上是未知的。更详细地了解进展性病变的病因将改善风险分层，以区分进展风险低的女性和可能快速进展为浸润性癌症的女性。我们认为，基因组印记基因（一组约50个已知的生长调节基因，其中只有一个等位基因通常是活跃的）的失调可能预测宫颈癌的进展。我们发现，大量的印记基因组表现出改变表达ICC与正常宫颈上皮。此外，控制IGF 2表达的两个调控区的甲基化分析显示，在CIN 2-CIN 3分类的标本中偏离正常，在浸润性癌症中偏离更大。总之，这些研究结果表明，印记基因在ICC中被解除管制，这些特征可能会改善CIN病例的检测。我们的中心假设是，在印记基因的印记调控元件的失调，可能受到环境暴露的影响，增加了感染“高危”HPV的妇女进展为宫颈癌的风险。我们已经显示了种族差异的影响，环境暴露的印记放松管制，因此，进一步假设，在非洲裔美国人和西班牙裔美国人的风险较高是由于种族/民族差异，这些基因的放松管制。我们的具体目标是：（1）确定已知印记基因的印记调节元件的失调是否与CIN 1进展为CIN 2+的风险增加相关，以及这种关联是否因种族/民族而异;（2）确定宫颈细胞中印记调节元件的异常甲基化是否与外周血细胞中发现的相似，提示早期事件;并与（i）转录表达和（ii）印记缺失相关;（3）评估宫颈细胞中已知印记基因的失调是否可用于在500例意义不确定的非典型鳞状细胞（ASCUS）病例中区分CIN 2+女性。为了实现这一目标，我们将招募并随访1,500名CIN 1女性和500名ASCUS女性，并检查12个基因的印迹调控元件处的异常甲基化标记物与CIN 1至CIN 2+进展之间的相关性。然后，我们将测试这些标记物的性能，以从500例ASCUS病例中识别CIN 2+病例。这项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已经导致癌症发病率和死亡率降低，但在美国每年仍有估计11，000例浸润性宫颈癌和40，000例原位癌病例被诊断，与白人相比，非裔美国人的发病率高60%，死亡率高2倍。我们将招募并随访1,500例CIN 1和500例不确定意义的非典型鳞状细胞（ASCUS），并检查12个基因的印记调控元件异常甲基化与进展为CIN 2或更糟之间的关联，然后测试这些标记物在ASCUS病例中的表现，独立于已知的辅助因子。这项研究的数据将阐明表观遗传失调在CIN 2+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.