Testing a candidate gene, conserved in early colon cancer among three mammalian species, for a role in field cancerization

Colorectal cancer is the third most common cancer in both incidence and mortality worldwide. The ability to identify disease in its early stages through screening colonoscopy and effectively treat individuals, exemplifies the importance of early detection. However, low compliance and continued high mortality rates demonstrate the importance of less invasive screening methods and a deeper understanding of early disease. The Dove Lab has undertaken a comparative approach, utilizing both a mouse and a rat model of early intestinal tumorigenesis for identification of genetic changes important for early tumorigenesis in humans. The ultimate goal of these studies is to translate laboratory findings to human patients. Whole genome microarray analysis in the mouse, the rat, and the human has identified a number of genomic changes between normal colonic epithelium and adenoma. My thesis work has focused on understanding genomic changes in common between these two model species and the human. Approaches of comparison between species has identified a strength of comparison using Boolean logic as well as higher-level GO Category comparison to overcome technical and biological variation between microarray studies. This comparison of species has identified one novel gene, Pde4b, that was previously unknown to play a role in early tumorigenesis. Work on Pde4b in the mouse has focused on its functional role in field cancerization and early tumorigenesis in spontaneous and inflammatory tumors. Pde4b plays a protective role in early tumor formation. We identified Pde4b as overrepresented in normal colonic epithelium in animals with colon tumors and further overrepresented in tumors. We have shown that removing Pde4b results in a dosage-dependent increase in colon tumors. This is the first time Pde4b has been shown to play a role in colon tumor formation. In work on Pde4b in an inflammatory mouse model, we showed that Pde4b plays a protective role in tumor formation and response to inflammation. Animals null for Pde4b demonstrate a Apc mutant-dependent lethality. Together, my work on overlap between species with a focus on Pde4b shows the potential of using multiple species to identify novel candidates. These discoveries may be used as a way to identify biomarkers and provides useful information to identify candidates with therapeutic application.