Observation of human colonic polyps by virtual colonoscopy has indicated several possible fates: regression, stasis, growth, or progression. Further, epidemiological studies and recent molecular genetic analyses of human colon cancer indicate that multiple alternative pathways and mutational signatures exist. These observations lead us to ask: does the fate of a colonic polyp reflect the pathway along which it has formed? We can address this question using our established murine models for familial colon cancer, the Min mouse and the Pirc rat, that enable longitudinal studies of polyp fate (Aim 1). The tumorigenesis pathways in these models will vary from one involving spontaneous somatic genetic changes (loss-of-heterozygosity), to that involving stochastic epigenetic silencing of the tumor suppressor locus Apc, and to another involving induced inflammation. Archived tumors will enable a quantitative molecular analysis of both the genome and epigenome by Pyrosequencing and of the transcriptome by Agilent microarray analysis (Aim 2). This set of longitudinal studies of polyps in both the Min mouse and Pirc rat is designed to yield three tangible products: """""""" An understanding of the relationships between the fate of an early polyp, its etiology, and its molecular markers using in vivo models that are optimized for signal/noise owing to inbred mammalian species in controlled environments. """""""" A permanent archive of biologically annotated tumor samples from maximally informative F1 genetic backgrounds. These will be available for retrospective molecular analysis of the tumor genome, epigenome, and transcriptome - by our laboratory and others in the field. """""""" A resultant set of classes of biological and molecular signatures that are conserved between two mammalian species, the mouse and rat. Conservation increases the probability of correlation with such signatures in the human for both diagnosis of early adenomas and prognosis of tumors with high neoplastic potential. An emergent set of human colonic polyps with known longitudinal profiles have been established by CT colonography. This resource permits an initial test of whether signatures gleaned from the controlled studies of subsets of mouse and rat tumors can be correlated with those of subsets of human colonic tumors (Aim 3). Though surely not the last step, this proposal constitutes this laboratory's first step at testing explicitly what informative correlations can be detected between animal models and human colon cancer. Signatures that can discriminate between tumors that vary in neoplastic potential are particularly important to discern.
No single experimental mammalian species can completely simulate the human. Therefore, we are using both a mouse model, Min, and a rat model, Pirc, to seek histological and molecular signatures conserved across mammalian species that can discriminate between early tumors that will grow and progress versus those that spontaneously arrest or even regress. A cohort of patients whose colonic neoplasms are being followed longitudinally by CT colonography provides a resource to test the relevance to human colon cancer of diagnostic and prognostic signatures discovered by controlled studies in these two animal models.
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