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

项目摘要。 Line-1(L1)元素是内源移动元素，可以自我复制并插入新的 在整个人类基因组中复制。当它们被插入编码外显子或其他功能时 基因中的重要位置，它们可以导致人类疾病，包括癌症。尽管L1是功能性的“源” 在成年体细胞组织中，元素通常通过甲基化而沉默，许多L1来源元素具有 已被发现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 和致癌基因。例如，我们确定了一种逃避体细胞抑制的高活性L1源元素 并通过突变APC抑癌基因启动结直肠癌(CRC) 一位非裔美国人的病人。重要的是，我们发现这种来源元素只在非洲和 散居海外的非洲人(包括非裔美国人)，这表明它可能对 这些种群。我们还发现了另一个类似的成分，它逃避了躯体的抑制，并产生了 这个病人的肿瘤中有额外的体细胞L1插入。第二个元素也只在 非洲人和散居海外的非洲人(包括非洲裔美国人)。在本提案中，我们将测试 假设这两个高活性的L1源元素(以及其他类似的L1元素)会增加风险 对于非裔美国人来说，与缺乏这些因素的白人对照队列相比，他们患上了结直肠癌。我们也 将检测这些元素在非裔美国人CRC中的甲基化状态和表达，以探索 他们逃避躯体压制的机制(S)。总体而言，这些研究将使我们能够评估 这些人群特有的L1源元素对非裔美国人构成的癌症风险。

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.