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

项目摘要。 LINE-1（L1）元件是内源性的移动的元件，其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上 在基因的重要位点，它们可以导致人类疾病，包括癌症。虽然功能L1“源” 在成人体细胞组织中，元件通常会因甲基化而沉默，许多L1源元件具有 已经鉴定出可以逃避体细胞阻遏并在肿瘤抑制基因中产生新的L1插入 和致癌基因。例如，我们鉴定了一个高度活跃的L1源元件，它可以逃避体细胞阻遏， 在正常结肠组织中，APC肿瘤抑制基因突变引发结直肠癌（CRC）， 一个非裔美国病人重要的是，我们发现这种来源元素只在非洲和 非洲散居人口（包括非洲裔美国人），这表明它可能对非洲裔美国人构成独特的癌症风险。 这些人口。我们还发现了另一个类似的元素，它可以逃避体细胞抑制， 在该患者的肿瘤中存在额外的体细胞L1插入。第二种元素也只在 非洲人和非洲侨民（包括非裔美国人）。在本提案中，我们将测试 假设这两个高度活跃的L1源元素（以及其他类似的L1元素）增加了风险 与缺乏这些因素的白色对照组相比，非裔美国人发生CRC的风险更高。我们也 将检查非裔美国人CRC中这些元件的甲基化状态和表达，以探索 它们逃避体细胞抑制的机制。总的来说，这些研究将使我们能够评估 这些人群特异性L1源元素对非裔美国人造成的癌症风险。

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.