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.

项目摘要 试点研究项目 结肠癌预后差异中的表观遗传因素和微生物组 TUFCCC：Jean-Pierre Issa，MD和Carmen Sapienza，PhD（联合领导人） HC：Frida Kleiman，PhD（共同负责人） 流行病学数据表明，年龄调整的癌症死亡率存在种族和/或族裔差异， 以及个别癌症的发病率和死亡率。可能有多种原因 这种差异，包括社会经济因素（SES），如教育，获得医疗保健，应用 早期检测方法和先进疗法的可用性。然而，结肠直肠癌的种族差异 癌症提供了一个迹象，表明生物学因素也可能在起作用。不仅结肠直肠 非裔美国男性和非裔美国女性的癌症死亡率高于白人男性 而非裔美国人患者患微卫星不稳定性癌症（一种 结果改善的癌症）和非裔美国人患者的肿瘤似乎具有明显的 突变谱我们的假设是，非洲裔美国人和 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 两组之间的差异。这一假设是基于我们实验室和其他实验室公布的数据， 包括鉴定癌症患者的正常结肠粘膜中的DNA甲基化差异， 以高灵敏度和特异性区分癌症患者和非癌症患者。甲基化 我们发现的差异发生在与癌症相关的遗传和表观遗传变化的基因中， 但也包括参与脂质和碳水化合物代谢的基因，这与 饮食因素影响结肠癌风险的观点。另外，我们最近的数据表明癌症- 肠道微生物组的相关改变，包括与 炎症在这个应用程序中，我们将执行分析，完全平行于我们以前发表的 分析和我们非常强大的初步数据来检验假设， 癌症是由正常粘膜中与种族相关的环境和遗传差异驱动的， 与肠道微生物组相互作用以改变癌症风险。我们将比较正常结肠的DNA甲基化组， 以种族分层的方式对癌症患者和非癌症患者的粘膜进行分类，以鉴定癌症正常结肠 “场效应”特征，并确定该特征是否与 影响基因表达的染色质变化。我们还将确定任何微生物组成分， 癌症富集和种族相关。这项研究将作为更多研究的探索性基础 针对结肠中与种族相关的遗传和表观遗传途径的机制研究 癌