The cancer genome is characterized by a myriad of genetic alterations that promote its growth and survival. In 5% of cancers, expansions and contractions at repetitive regions called short tandem repeat sequences lead to microsatellite instability. Although variations in TR sequences are implicated in over 40 human diseases, they remain underexplored in cancer due to the limitations of conventional bioinformatic tools. Our recent work identified recurrent repeat expansions (rREs) as an unexplored source of genetic variation in cancer (Erwin et al., Nature 2023). A comprehensive understanding of repeat variation in cancer is essential for developing novel TR-targeting therapeutics. In this a...
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The cancer genome is characterized by a myriad of genetic alterations that promote its growth and survival. In 5% of cancers, expansions and contractions at repetitive regions called short tandem repeat sequences lead to microsatellite instability. Although variations in TR sequences are implicated in over 40 human diseases, they remain underexplored in cancer due to the limitations of conventional bioinformatic tools. Our recent work identified recurrent repeat expansions (rREs) as an unexplored source of genetic variation in cancer (Erwin et al., Nature 2023). A comprehensive understanding of repeat variation in cancer is essential for developing novel TR-targeting therapeutics. In this application for a CPRIT award, I propose a multidisciplinary approach to investigate the role of repeat variations in cancer, including their functional consequences. The primary goals of this grant are: 1. Catalog recurrent repeat contractions and repeat mini-mutations in cancer to create a broadly-useful dataset for the cancer community. 2. Determine the function of recurrent repeat contractions and repeat mini-mutations identified in our analysis to elucidate their role in cancer. 3. Develop repeat-targeting molecules to test the potential for targeting recurrent variations, with an emphasis on renal cell carcinoma. Baylor College of Medicine offers the ideal environment for this research due to its state-of-the-art facilities, renowned faculty, and interdisciplinary cancer research environment. My long-term goal is to enhance precision medicine approaches for cancer therapy by gaining a deeper understanding of variation in repetitive DNA sequences. This project will contribute significantly to our knowledge of cancer genomics and enable the development of innovative diagnostics and therapeutics targeting repeat variants.
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