L1 element mutagenesis as a driver of epithelial cancers in African Americans

L1 元件突变是非裔美国人上皮癌的驱动因素

• 批准号: 10350837
• 负责人: Scott E Devine
• 金额: $ 21.67万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350837
• 关键词: APC gene; Adult; African; African American; African American population; Carcinoma; Chromosome 14; Chromosome 17; Code; Colon; Colonic Neoplasms; Colorectal Cancer; DNA Insertion Elements; Elements; Exons; Exploratory/Developmental Grant; Funding Opportunities; Genes; Genome; Human Genome; L1 Elements; Malignant Neoplasms; Measures; Mediating; Methylation; Mission; Mutagenesis; Mutate; Mutation; Nature; Normal tissue morphology; Oncogenes; Patients; Population; Repression; Risk; Risk Factors; Site; Source; Testing; The Cancer Genome Atlas; Tissues; Tumor Suppressor Genes; Tumor Tissue; United States National Institutes of Health; Variant; Woman; cancer risk; cohort; colorectal cancer risk; driver mutation; exome; experimental study; high reward; high risk; human disease; innovation; insight; novel; offspring; promoter; tumor; tumorigenesis

Project Summary. LINE-1 (L1) elements are endogenous mobile elements that can replicate themselves and insert new copies throughout the human genome. When they are inserted into coding exons or other functionally important sites in genes, they can cause human diseases, including cancers. Although functional L1 “source” elements are typically silenced by methylation in adult somatic tissues, a number of L1 source elements have been identified that can evade somatic repression and generate new L1 insertions in tumor suppressor genes and oncogenes. For example, we identified a highly active L1 source element that evaded somatic repression in normal colon tissues and initiated colorectal cancer (CRC) by mutating the APC tumor suppressor gene in an African American patient. Importantly, we found that this source element was only found in African and African-diaspora populations (including African Americans), suggesting that it may pose a unique cancer risk to these populations. We also identified another similar element that evaded somatic repression and generated additional somatic L1 insertions in the tumor of this patient. This second element also was only found in African and African-diaspora populations (including African Americans). In this proposal, we will test the hypothesis that these two highly active L1 source elements (and other L1 elements like them) increase the risk for African Americans to develop CRC compared to White control cohorts who lack these elements. We also will examine the methylation status and expression of these elements in African American CRCs to explore the mechanism(s) by which they evade somatic repression. Overall, these studies will allow us to evaluate the cancer risk that is posed by these population-specific L1 source elements to African Americans.

项目摘要。 第1行（L1）元素是内源性移动元素，可以复制并插入新的移动元素 整个人类基因组的副本。当它们插入编码外显子或其他功能时 基因的重要部位，它们可能引起人类疾病，包括癌症。尽管功能性L1“源” 元素通常被成年体细胞组织中的甲基化沉默，许多L1源元素具有 被鉴定出可以逃避体细胞表示并在肿瘤抑制基因中产生新的L1插入 和致癌基因。例如，我们确定了一个高度活跃的L1源元素，该元素逃避了体细胞表示 在正常结肠组织中，通过突变APC抑制基因中的结肠癌（CRC） 非裔美国人患者。重要的是，我们发现此源元素仅在非洲和 非洲 - 河畔普拉普拉族人口（包括非裔美国人），表明它可能对癌症构成独特的癌症风险 这些人群。我们还确定了另一个逃避躯体表示并生成的类似元素 该患者肿瘤中的其他体细胞L1插入。第二个元素也仅在 非洲和非洲裔人口（包括非洲裔美国人）。在此提案中，我们将测试 假设这两个高度活跃的L1源元素（以及其他L1元素）增加了风险 与缺乏这些元素的白人对照组相比，非洲裔美国人要发展CRC。我们也是 将检查这些元素在非裔美国人CRC中的甲基化状况和表达 他们逃避躯体代表的机制。总体而言，这些研究将使我们能够评估 这些特定人群的L1源元素对非裔美国人的癌症风险。