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

项目摘要 全面研究项目2-结肠癌 结直肠癌DNA甲基化表型改变与种族差异的关系 TUfccc：卡门·萨皮恩扎博士(联席主管)和贾亚什里·戈什博士(ESI联席主管) HC：Frida E.Kleiman，博士(联席领导) 非裔美国人(AA)的结直肠癌(CRC)发病率和死亡率高得不成比例 与高加索美国人(CA)相比。目前的非侵入性筛查工具，如粪便潜血测试 (FOBT)或粪便DNA标记物，在癌症发生后检测。更有效的预防和治疗手段 风险较高的个体，如结肠镜检查或内窥镜检查，是有创的，不太受欢迎和主观的，目前 与CA相比，AA对这些筛查工具的吸收较低。因此，早期和早期的鉴定 目的探讨区分结直肠癌高危人群正常结肠粘膜与结直肠癌高危人群的生物标志物 低风险可能会减少结直肠癌的种族差异。在我们之前的U54试点项目(第一周期)中，我们已经确定 一组具有高度破坏的表观基因组显示异常DNA甲基化模式的患者 他们的正常粘膜被鉴定为“异常甲基化表型”(OMP)。我们已经能够显著地 将这种表型与结直肠癌患者联系起来，而不是健康对照。此外，再生障碍性结直肠癌患者表现出更多 患有OMP的可能性是CA患者的两倍多。在当前周期中，我们建议确定流行率 在更大一组特定目标的OMP患者中，AA(150个结直肠癌和200个对照)和CA(150个结直肠癌 和200个对照)。在特定的目标1B中，我们将阐明OMP对 使用患者衍生的有机化合物(PDO)进行结直肠癌的致瘤。在具体目标2中，我们还将确定是否 再生障碍性贫血患者中受OMP影响的基因富含黑人/祖先信息的遗传变异。以特定的目标 3、我们将确定环境因素和社会决定因素是否影响OMP在 AA组。打破系统性障碍：我们的猎人学院/坦普尔/狐狸大通跨学科 由长凳科学家、临床医生和社区外展科学家组成的团队处于独特的地位，可以减少系统性 在表观遗传学研究中导致AA群体代表性不足的障碍。这个项目 通过将氨基酸纳入表观遗传学研究并开发定量和侵入性较小的方法来解决数据差距 可能使AA增加结直肠癌筛查的筛查测试，并减少结肠癌 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.