Cytosine Deamination Adducts and Cancer Etiology

DNA damage drives human genetic disease including cancer. Exogenous chemicals and endogenous reactive molecules can damage DNA bases, forming adducts. Unrepaired DNA adducts can block DNA synthesis or miscode during polymerase-mediated replication. The landscape of mutations observed in human cancers is dominated by C:G to T:A transition mutations. A major cause of these mutations is the hydrolytic deamination of cytosine and cytosine analogs in DNA to their corresponding uracil analogs, generating a class of cytosine deamination adducts, xU. Endogenous DNA adducts such as xU have proven more difficult to study due to the similarity of these adducts to normal DNA constituents as well as their formation in normal, unperturbed cells and tissues. 

Our goal is to develop innovative state-of-the-art methods to measure the types of DNA damage that cause the most common mutations in human cancers. We aim for these techniques to become clinically useful approaches to examine the damage history of a given tissue, and provide an estimate as to how far the damage has progressed toward the development of tumors. The anticipated results will shed new light on cancer etiology and potentially direct approaches to reduce cancer incidence and provide earlier detection.