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

项目摘要 完整研究项目2 -结肠癌 结直肠癌DNA甲基化表型改变与种族差异 TUFCCC：Carmen Sapienza博士（联合负责人）和Jayashri Ghosh博士（联合负责人，ESI） 弗里达·E. Kleiman，PhD（共同负责人） 非裔美国人（AA）的结直肠癌（CRC）发病率和死亡率不成比例地高 美国白人（Caucasian Americans，CA）目前的非侵入性筛查工具，如粪便潜血试验 FOBT或粪便DNA标记，在癌症发生后检测癌症。更有效的预防和治疗 高风险个体，如结肠镜检查或内窥镜检查，是侵入性的，不太受欢迎和主观， 这些筛选工具的吸收率在AA中低于CA。因此，早期识别和 区分CRC高危个体与CRC高危个体的正常结肠粘膜的客观生物标志物， 低风险可能会减少CRC的种族差异。在我们之前的U 54试点项目（周期1）中，我们已经确定了 一个具有高度破坏的表观基因组的患者亚组显示出异常的DNA甲基化模式， 其正常粘膜，鉴定为“异常甲基化表型”（OMP）。我们已经能够显著地 与健康对照相比，将这种表型与CRC患者相关联。此外，AA CRC患者出现更多 是CA患者患OMP的可能性的两倍多。在本周期中，我们建议确定 在特定目标1A中，AA（150例CRC和200例对照）和CA（150例CRC）的较大患者组中的OMP 200控制）。在具体目标1B中，我们将阐明OMP对 使用患者衍生的类器官（PDO）的CRC肿瘤发生。在具体目标2中，我们还将确定 AA患者中受OMP影响的基因富含Black/black信息遗传变异。具体目标 3.我们将确定环境因素和社会决定因素是否影响OMP的频率， AA组。打破包容性的系统性障碍：我们的亨特学院/坦普尔/福克斯蔡斯跨学科 由实验室科学家、临床医生和社区外展科学家组成的团队处于独特的地位， 导致AA人群在表观遗传学研究中代表性不足的障碍。这个项目 通过在表观遗传学研究中纳入AA，并通过开发定量和侵入性较小的方法， 筛选测试，这将有可能使AA增加CRC筛查的吸收，并减少结肠癌的发生。 癌症差异

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.