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 phenotypes more extree 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 GI tumor phenotypes governed by allelic variation. 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 all 3 GI cancers in humans. The use of the CC lines coupled with the use of our unique, long-lived, but sensitized congenic strain background provides an innovative approach to the study of GI cancers.
One form of a gene can make a person resistant to developing tumors, while a different form of the same gene can make another person susceptible to developing tumors. This research is designed to identify new models of intestinal cancer and discover the underlying genetic variants that influence cancer development. Our ultimate goal is to use these genes for assessing cancer risk and design preventive therapeutics to protect individuals from cancer.
