Pilot Research Project Epigenetic Factors and the Microbiome in Disparities in Colon Cancer Outcomes

试点研究项目表观遗传因素和微生物组在结肠癌结果差异中的作用

• 批准号: 10018487
• 负责人: FRIDA E KLEIMAN
• 金额: $ 2.11万
• 依托单位: HUNTER COLLEGE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10018487
• 关键词: Address; Adenomatous Polyps; Affect; African; African American; Age; Aging; Americas; Animal Model; Biology; Cancer Patient; Candidate Disease Gene; Carbohydrates; Categories; Caucasians; Cell Line; Chromatin; Colon; Colon Carcinoma; Colonoscopy; Colorectal Cancer; DNA; DNA Methylation; Data; Diet; Dietary Factors; Doctor of Philosophy; Early Diagnosis; Education; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Ethnic Origin; Gene Expression; Gene Silencing; Genes; Genetic; Genotype; Hispanics; Incidence; Individual; Inflammation; Inflammatory; Laboratories; Lead; Link; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Methylation; Microsatellite Repeats; Mismatch Repair; Mucous Membrane; Mutation; Normal tissue morphology; Outcome; Pathogenicity; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Population; Process; Publishing; Race; Research Project Grants; Sensitivity and Specificity; Single Nucleotide Polymorphism; Site; Social Policies; Socioeconomic Factors; Testing; Time; Tissues; Transcript; Woman; base; cancer health disparity; cancer risk; cancer type; carbohydrate metabolism; colon cancer patients; colon cancer risk; colorectal cancer risk; education access; epidemiologic data; ethnic difference; gut microbiome; health care availability; histone modification; improved outcome; lipid metabolism; malignant breast neoplasm; men; methylome; microbiome; microbiome alteration; microbiome components; microorganism; mortality; premalignant; racial and ethnic; racial difference; racial disparity; screening; tumor

PROJECT SUMMARY Pilot Research Project Epigenetic Factors and the Microbiome in Disparities in Colon Cancer Outcomes TUFCCC: Jean-Pierre Issa, MD and Carmen Sapienza, PhD (Co-Leaders) HC: Frida Kleiman, PhD (Co-Leader) Epidemiological data have demonstrated race and/or ethnicity differences in age-adjusted mortality for cancer, overall, and for the incidence and mortality rates of individual cancers. There are likely multiple reasons for such disparities, including socioeconomic factors (SES), such as education, access to healthcare, application of early detection methods and availability of advanced therapies. However, racial disparities in colorectal cancer provide one indication that biology-based factors are also likely to be at play. Not only are colorectal cancer mortality rates for African American men and African American women higher than for Caucasian men and women but African American patients appear less likely to develop microsatellite instable cancers (a type of cancer with improved outcomes) and tumors from African American patients appear to have a distinct mutation profile. Our hypothesis is that much of the racial disparity between African Americans and Caucasians in colon cancer incidence and outcomes are due to environmental and/or genetic differences between the two groups. This hypothesis is based on published data from our laboratories as well others, including the identification of DNA methylation differences in the normal colon mucosa of cancer patients that distinguish cancer patients from patients without cancer with high sensitivity and specificity. The methylation differences we identified occur in genes in which cancer-associated genetic and epigenetic changes have been identified but also include genes involved in the metabolism of lipids and carbohydrates, consistent with the notion that dietary factors influence risk for colon cancer. In addition, our more recent data identifies cancer- associated alterations to the gut microbiome, including increases in pathogenic species associated with inflammation. In this application, we will perform analyses that are exactly parallel to our previously published analyses and to our very strong preliminary data to test the hypothesis that the racial disparities in colon cancer are driven by race-associated environmental and genetic differences in the normal mucosa that interact with the gut microbiome to alter cancer risk. We will compare the DNA methylome of normal colon mucosa of cancer patients and patients without cancer in a race-stratified way to identify a cancer normal colon “field-effect” signature that is race-associated and determine whether this signature is associated with chromatin changes that affect gene expression. We will also identify any microbiome components that are cancer-enriched and race associated. This study will serve as the exploratory groundwork for more mechanistic studies that will target the genetic and epigenetic pathways identified as race-associated in colon cancer.

项目总结 先导研究项目 表观遗传因素和微生物组在结肠癌预后差异中的作用 TUfccc：Jean-Pierre Issa医学博士和Carmen Sapienz博士(联合领导) HC：Frida Kleiman，博士(联席领导) 流行病学数据表明，年龄调整后的癌症死亡率存在种族和/或民族差异， 总体而言，以及个别癌症的发病率和死亡率。可能有多种原因导致 这种差异，包括社会经济因素(SES)，如教育、获得医疗保健的机会、应用 早期检测方法和先进疗法的可获得性。然而，结直肠癌中的种族差异 癌症提供了一个迹象，表明基于生物学的因素也可能在发挥作用。不仅是结直肠癌 非洲裔美国男性和非洲裔美国女性的癌症死亡率高于高加索男性 而非裔美国人患者以外的女性似乎不太可能患上微卫星不稳定性癌症(一种 预后改善的癌症患者)和来自非裔美国人患者的肿瘤似乎有明显的 突变特征。我们的假设是，非裔美国人和非裔美国人之间的种族差距 高加索人结肠癌的发病率和预后是由于环境和/或遗传差异造成的 在这两组人之间。这一假设是基于我们实验室和其他实验室公布的数据， 包括鉴定癌症患者正常结肠粘膜中DNA甲基化的差异 以高度的敏感性和特异性区分癌症患者和非癌症患者。甲基化 我们确定的差异发生在与癌症相关的基因和表观遗传学变化 已识别的，但也包括参与脂肪和碳水化合物代谢的基因，与 饮食因素影响结肠癌风险的概念。此外，我们最近的数据确定了癌症- 肠道微生物群的相关变化，包括与以下疾病相关的致病物种增加 发炎。在此应用程序中，我们将执行与之前发布的完全平行的分析 分析和我们非常强大的初步数据来测试这一假设，即结肠的种族差异 癌症是由正常粘膜中与种族相关的环境和遗传差异所驱动的 与肠道微生物群相互作用，改变癌症风险。我们将比较正常结肠的DNA甲基组 用种族分层的方法识别癌症患者和非癌症患者的正常结肠粘膜 与种族关联的“场效应”签名，并确定此签名是否与 影响基因表达的染色质变化。我们还将确定任何符合以下条件的微生物组组件 癌症患者和种族相关者。这项研究将作为更多的探索基础 机制研究将以结肠中被确认为种族相关的遗传和表观遗传途径为目标 癌症。