Using the Collaborative Cross for Model Studies of Intestinal Cancer

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Using the Collaborative Cross for Model Studies of Intestinal Cancer Gastrointestinal (GI) cancers are worldwide health issues that are both highly prevalent and deadly. The ability to understand the genetic factors influencing the change of normal stomach, small intestine, and colorectal tissues towards the initiation, growth and progression to cancer is essential to the goals of precision medicine. As with every cancer, being able to identify people at risk before the cancer appears provides the greatest opportunity to intervene and prevent the development of life-threatening disease. To better model human disease, the Collaborative Cross (CC) was generated and has captured the tremendous genomic variation present within one mammalian species, the mouse. The CC are recombinant inbred (RI) lines created from the genomic contributions of 8 inbred founder strains, chosen because of their evolutionary diversity with each other. The unique combination of alleles within the different CC lines facilitates: 1) the identification of disease phenotypes more extreme than have been observed in common inbred laboratory strains, and 2) the opportunity for high resolution mapping of loci influencing complex traits. Our studies represent an avenue to investigate, characterize, and quantitate GI tumor phenotypes within individual CC lines. We propose to use a sensitized background, namely a mutation in the adenomatous polyposis coli (Apc) gene coupled with a resistant Mom2R allele, and mate these mice with the CC lines in a one-step cross to screen for dominant modifiers that lead to increased tumorigenesis or altered tumor profiles. We have incorporated a mutant Apc allele because the APC gene is one of the top 5 genes mutated in stomach, small intestine, and colorectal cancers in humans. The use of the CC lines coupled with the use of our unique, long-lived, but sensitized congenic strain brings an innovative approach to the in vivo study of GI cancers.