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: 10543470
• 负责人: Scott E Devine
• 金额: $ 17.7万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543470
• 关键词: APC gene; Adult; African; African American; African American population; Carcinoma; Chromosome 14; Chromosome 17; Code; Colon; 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 initiation; 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。 LINE-1 (L1) 元件是内源性移动元件，可以自我复制并插入新的元件 当它们被插入编码外显子或其他功能时。 虽然 L1 是功能性的“来源”，但它们可能导致人类疾病，包括癌症。 元件通常在成体体细胞组织中通过甲基化而沉默，许多 L1 源元件具有 已被鉴定可以逃避体细胞抑制并在肿瘤抑制基因中产生新的 L1 插入 例如，我们发现了一种高度活跃的 L1 源元件，它可以逃避体细胞抑制。 正常结肠组织中的 APC 抑癌基因发生突变，引发结直肠癌 (CRC) 重要的是，我们发现这种来源元素仅存在于非洲裔美国人中。 非洲裔侨民（包括非裔美国人），表明它可能对以下人群构成独特的癌症风险 我们还发现了另一个类似的元素，它逃避了躯体抑制并产生了。 该患者的肿瘤中存在额外的体细胞 L1 插入，这第二个元素也仅在以下细胞中发现。 在本提案中，我们将测试非洲人和非洲裔侨民（包括非裔美国人）。 假设这两个高度活跃的 L1 源元素（以及其他类似的 L1 元素）会增加风险 与缺乏这些要素的白人对照人群相比，非洲裔美国人更容易患上结直肠癌。 将检查非裔美国人 CRC 中这些元素的甲基化状态和表达，以探索 总的来说，这些研究将使我们能够评估它们逃避躯体抑制的机制。 这些特定人群的 L1 源元素对非裔美国人造成的癌症风险。