Disparities in cervical cancer precursors and deregulation of imprinted genes

宫颈癌前兆的差异和印记基因的失调

• 批准号: 8265756
• 负责人: Cathrine Hoyo
• 金额: $ 8.64万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265756
• 关键词: Accounting; Address; Adherence; African; African American; Age-Years; Alleles; Animals; Anxiety; Atypical Squamous Cell; Blood Cells; Blood Circulation; CDKN1C gene; Carcinoma in Situ; Caring; Cells; Cervical; Cervical Cancer Screening; Cervical Intraepithelial Neoplasia; Cervix carcinoma; Classification; Clinic; Contraceptive Usage; Cytopathology; Data; Dependence; Detection; Development; Diagnosis; Early Diagnosis; Early treatment; Environmental Exposure; Epidemiologic Studies; Epigenetic Process; Epithelium; Ethnic Origin; Etiology; Event; Exhibits; Exposure to; GRB10 gene; Gene Expression; Genes; Genome; Genotype; Growth; H19 gene; HPV-High Risk; Haploidy; Hispanics; Human papilloma virus infection; Human papillomavirus 16; IGF2 gene; Incidence; Infection; Inherited; Lesion; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Methylation; Minority; Modification; Morbidity - disease rate; Nucleic Acid Regulatory Sequences; Oncogene Deregulation; Oral Contraceptives; PLAGL1 gene; Pap smear; Patients; Pattern; Perinatal; Perinatal Exposure; Play; Population; Prevalence; Promoter Regions; Race; Recruitment Activity; Regulation; Regulator Genes; Regulatory Element; Relative (related person); Relaxation; Research; Research Priority; Risk; Role; SNRPN; Sampling; Screening procedure; Sensitivity and Specificity; Specimen; Staging; Stratification; Testing; Time; Tissue Differentiation; Tissue-Specific Gene Expression; Triage; Tumor Suppressor Genes; United States; United States National Institutes of Health; Universities; Variant; WT1 gene; Woman; Work; base; cancer diagnosis; cancer health disparity; cancer initiation; cancer risk; cervical and uterine cancer; cigarette smoking; cofactor; cost; ethnic difference; follow-up; high risk; imprint; improved; insight; intraepithelial; mortality; parity; performance tests; peripheral blood; prevent; promoter; public health relevance; treatment program; tumor growth; tumor progression; years of life lost

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.

描述（由申请人提供）：尽管宫颈上皮内病变（CIN）及其侵略性治疗导致宫颈癌的发病率和死亡率降低，但估计有11,000例入侵性宫颈癌（ICC）病例和40,000例现场（CIS（CIS）（CIS）的40,000例继续诊断为美国的纽约州。与白人相比，非洲裔美国人的ICC发病率高出60％，死亡率高两倍。尽管筛查速率可比，但在发病率和死亡率上的这种不同的率是检测前体病变，“高风险”人乳头瘤病毒（HPV）感染，病因学剂和诸如吸烟等副因素的可比患病率。这种差异的原因在很大程度上是未知的。对病变的病因的更详细的理解将改善风险分层，以区分妇女的进展较低风险从可能迅速发展为侵入性癌症的妇女。我们认为，基因组印迹基因的放松管制，这是一组大约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，可能会预测宫颈癌的发展。我们发现，在ICC和正常宫颈上皮中，一组烙印基因表现出改变的表达。此外，对控制IGF2表达的两个调节区域的甲基化分析显示，在具有CIN2-CIN3分类的标本中，正常情况偏离侵入性癌症的偏差。总之，这些发现表明，印迹基因在ICC中受管制，这些特征可能会改善对CIN病例可能进行的检测。我们的核心假设是，对印迹基因的烙印监管元素的放松管制，可能受环境暴露的影响，增加了感染“高风险” HPV的妇女中宫颈癌进展的风险。我们已经显示出种族差异对环境暴露对烙印放松管制的影响，因此进一步假设，非裔美国人和西班牙裔的风险较高是由于这些基因放松管制的种族/种族差异所致。我们的具体目的是：（1）确定已知印迹基因的烙印调节要素的放松管制是否与CIN1向CIN2+进展的风险增加有关，以及这种关联是否因种族/种族而变化； （2）确定宫颈细胞中烙印调节元件的异常甲基化是否与外周血细胞中发现的甲基化相似，这表明早期事件；并与（i）转录表达和（ii）失去印迹； （3）评估是否可以使用对宫颈细胞中已知的印迹基因的放松管制来区分500个具有不确定意义（ASCUS）病例的非典型鳞状细胞中的CIN2+女性。为了解决目标，我们将招募和关注1,500名CIN1和500名ASCUS的女性，并检查在12个基因的印记调节元素和从CIN1到CIN2+的烙印的异常甲基化标记之间的关联。然后，我们将测试这些标记的性能，以识别500例ASCUS病例中的CIN2+病例。拟议研究的数据将改善分类决策，并降低ICC发病率和死亡率的差异。 公共卫生相关性：尽管对预防宫颈癌的上皮内病变进行筛查导致癌症的发病率和死亡率降低，但估计有11,000例入侵性宫颈癌和40,000例现场癌症在美国每年继续诊断出40％的美国，而在美国的发病率更高，而在非洲裔美国人中，美国的发病率更高，死亡率更高，> 2次。我们将招募并遵循1,500例CIN1和500例不确定意义的非典型鳞状细胞（ASCUS），并检查在12个基因的印迹调节元件上异常的甲基化与CIN2或更糟的进展，然后在Ascus病例中测试这些标记的性能，在Ascus案例中的性能，独立于已知的共同因子。这项研究的数据将阐明表观遗传放松管制在CIN2+中的作用，并为分类决定提供信息，从而降低了宫颈癌发病率和死亡率的差异。