Genomic instability is an essential component in the development of colorectal cancer, facilitating those several mutations which combine during tumor progression to yield the malignant phenotype, as well as a multitude of other irrelevant genomic alterations. The molecular underpinnings of genomic instability in sporadic cancer remain poorly understood. Our goals are to understand genomic instability, measure such instability in a clinical setting, and ultimately develop means of arresting it. Human colorectal tumor progression provides the system of study. The objectives are to learn: (1.) What are the break and re-ligation points associated with genomic instability in tumor cell DNA? Cloning rearranged inter-(simple sequence repeat) PCR products and comparing their sequences to their normal counterpart should reveal how they arose. (2.) What factors drive intrachromosomal genomic instability in sporadic colorectal cancer? Promising early results indicating involvement of an endonuclease will be refined. (3.) What is the anoxia-inducible endonuclease associated with genomic instability? Once the endonuclease is identified rigorously, we will investigate if regulated overexpression of it in transfected cells can drive instability in PALA assays. (4.) At what stage of colorectal tumor progression does genomic instability first appear; does it increase in steps as multiple factors come into play? (5.) Can we suppress genomic instability with anti-inflammatory agents which suppress the anoxia-inducible endonuclease?
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