Full Research Project 2: Changes in DNA methylation phenotype in CRC associated with racial disparities

完整研究项目 2：CRC 中 DNA 甲基化表型的变化与种族差异相关

• 批准号: 10757260
• 负责人: CARMEN SAPIENZA
• 金额: $ 29.23万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10757260
• 关键词: Address; Affect; African; African American population; African ancestry; Biological; Biological Markers; Black race; Blood specimen; Cancer Detection; Cancer Etiology; Caucasians; Cessation of life; Characteristics; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; Community Outreach; Consent; DNA Markers; DNA Methylation; Data; Development; Diet; Doctor of Philosophy; Early identification; Endoscopy; Environment; Environmental Risk Factor; Epigenetic Process; Exhibits; Fecal occult blood; Frequencies; Gene Expression; Genes; Genetic; Incidence; Individual; Intervention; Malignant Neoplasms; Measures; Methylation; Modeling; Molecular; Mucous Membrane; Neighborhoods; Organoids; Outcome; Patients; Phenotype; Pilot Projects; Polyps; Population; Positioning Attribute; Prevalence; Prevention; Preventive treatment; Procedures; Quantitative Trait Loci; Questionnaires; Recording of previous events; Research Project Grants; Risk; Saliva; Scientist; Screening for cancer; Screening procedure; Subgroup; Testing; Time; United States; University Hospitals; Variant; Woman; adenoma; biobank; cancer health disparity; cancer risk; caucasian American; college; colon cancer patients; colorectal cancer risk; colorectal cancer screening; disparity elimination; disparity reduction; early detection biomarkers; epigenome; experience; genetic variant; high risk; high risk population; improved outcome; in vitro Model; men; methylation pattern; mortality; mortality risk; negative affect; patient population; patient subsets; peripheral blood; pre-clinical; predictive marker; racial disparity; randomized trial; research study; saliva sample; screening; social determinants; socioeconomics; systemic barrier; tool; tumorigenesis; uptake

Project Summary Full Research Project 2 – Colon Cancer Changes in DNA methylation phenotype in CRC associated with racial disparities TUFCCC: Carmen Sapienza, PhD (Co-Leader) and Jayashri Ghosh, PhD (Co-Leader, ESI) HC: Frida E. Kleiman, PhD (Co-Leader) Colorectal cancer (CRC) incidence and mortality rates are disproportionately higher in African Americans (AA) compared to Caucasian Americans (CA). Current non-invasive screening tools, such as fecal occult blood tests (FOBT) or fecal DNA markers, detect cancer after it occurs. More effective tools for prevention and treatment of higher risk individuals, such as colonoscopy or endoscopy, are invasive, less popular and subjective, and current uptake of these screening tools is lower among AA compared to CA. Therefore, identification of early and objective biomarkers that distinguish normal colon mucosa of individuals at high risk for CRC from individuals at low risk might decrease racial disparities in CRC. In our previous U54 Pilot project (Cycle 1), we have identified a subgroup of patients having highly disrupted epigenomes displaying abnormal DNA methylation patterns in their normal mucosa, identified as “Outlier Methylation Phenotype” (OMP). We have been able to significantly associate this phenotype with CRC patients over healthy controls. Furthermore, AA CRC patients appear more than twice as likely as CA patients to have OMP. In the current cycle, we propose to determine the prevalence of OMPs in a larger group of patients in Specific Aim 1A, both AA (150 CRC and 200 controls) and CA (150 CRC and 200 Controls). In Specific Aim 1B, we will elucidate biological mechanisms for the contribution of OMP to CRC tumorigenesis using patient derived organoids (PDO). In Specific Aim 2, we will also determine whether OMP - affected genes in AA patients are enriched in Black/Ancestry-informative genetic variants. In Specific Aim 3, we will determine whether environmental factors and social determinants influence the frequency of OMP in AA groups. Break Systemic Barriers to Inclusion: Our Hunter College/Temple/Fox Chase interdisciplinary team of bench scientists, clinicians and community outreach scientists is in a unique position to reduce systemic barriers that lead to underrepresentation of the AA population in epigenetic research studies. This project addresses data gaps by including AAs in the epigenetic studies and by developing quantitative and less invasive screening tests that will potentially enable AAs to increase the uptake of CRC screening, and reduce colon cancer disparities.

项目摘要 完整的研究项目2 - 结肠癌 与种族差异相关的CRC中DNA甲基化表型的变化 TUFCCC：Carmen Sapienza，博士（共同领导）和Jayashri Ghosh博士（ESI共同领导） HC：Frida E. Kleiman，博士（共同领导） 非洲裔美国人（AA）的结直肠癌（CRC）发病率和死亡率较高 与白人美国人（CA）相比。当前的非侵入性筛查工具，例如粪便神秘血液检查 （FOBT）或粪便DNA标记，在发生癌症后检测到癌症。预防和治疗的更有效的工具 较高的风险个体，例如结肠镜检查或内窥镜检查，具有侵入性，不流行和主观，并且当前 与CA相比，AA中这些筛选工具的吸收较低。因此，识别早期和 客观的生物标志物，区分CRC高风险的个体的正常结肠粘膜和个人 低风险可能会降低CRC中的种族分布。在我们以前的U54试点项目（周期1）中，我们已经确定了 一组高度破坏的表活性的患者，显示出异常的DNA甲基化模式 它们的正常粘膜被确定为“异常甲基化表型”（OMP）。我们已经能够显着 将此表型与CRC患者相关联，与健康对照组相关。此外，AA CRC患者看起来更多 具有OMP的可能性是CA患者的两倍。在当前周期中，我们建议确定患病率 在特定AIM 1A中，较大的患者中的OMP，AA（150 CRC和200个对照）和CA（150 CRC） 和200个控件）。在特定的目标1B中，我们将阐明生物学机制，以便OMP对 使用患者衍生的类器官（PDO）的CRC肿瘤发生。在特定目标2中，我们还将确定是否 AA患者的OMP - 受影响的基因富含黑色/祖先信息遗传变异。在特定目标中 3，我们将确定环境因素和社会决定者是否会影响OMP的频率 AA组。纳入全身障碍：我们的猎人学院/寺庙/福克斯大通跨学科 长凳科学家，临床医生和社区外展科学家团队处于独特的位置，可以减少系统性 在表观遗传学研究中导致AA人群不足的障碍。这个项目 通过在表观遗传学研究中包括AA并开发定量和侵入性较小的来解决数据差距 筛选测试可能会使AAS增加CRC筛选的吸收并降低颜色 癌症差异。