Friday, April 19, 2024
4/19/2024
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.
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