The broad, long-term objective of the proposed research is to determine if alterations in base excision repair(BER) genes that exist in the normal population and in tumors lead to phenotypes that could be linked to theetiology of cancer or to treatment response.
The specific aims of the application are to test the hypothesisthat polymorphisms in BER genes lead to cellular transformation, to test the hypothesis that BER variantsarising in the normal population and in tumors lead to genomic instability, and to test the hypothesis thatBER protein variants affect cancer treatment. To test these hypotheses we will take a combined genetic andbiochemical approach. We will express the variant BER proteins in cells and determine whether they inducefocus formation, anchorage independent growth, and tumors in mice. We will determine if expression of thevariants in cells induces mutations, and characterizethe types of mutations they induce. We will determine ifthe variants are differentially sensitive to various cancer treatments, including ionizing radiation andalkylating agents, the latter in collaboration with Project 1. We will also characterize the drug sensitivity ofcells in which multiple DMA repair pathways are compromised, in collaboration with Projects 1, 2, and 4. Thisproposal has the potential to further our understanding of the relationship between BER variants and canceretiology, and to provide mechanistic insights into the role of aberrant BER in cancer onset and treatment.Because BER is responsible for the repair of 10,000 lesions per cell per day and is a highly coordinatedprocess, we suspect that even minor imbalances in this system will impact cancer etiology. A thoroughunderstanding of BER variants in people will also serve as the basis for a future study of environmentalaspects of cancer promotion and progression within the context of these BER variants and has the potentialto provide important insight on lifestyle choices regarding cancer prevention.
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