The quest for genes influencing susceptibility or resistance to cancer has been a major undertaking by the scientific community. Every year tens of thousands of individuals in the United States are affected by small intestine and colorectal cancers (CRC). Although environmental factors play a role in disease etiology, uncovering underlying genetic factors is imperative in risk assessment and for developing preventative measures and novel therapeutics for treatment. The adenomatous polyposis coli (APC) tumor suppressor gene is mutated in Familial Adenomatous Polyposis (FAP), an inherited disorder that predisposes individuals to developing polyps in their intestinal tract and which eventually leads to cancer. Mouse models have served as valuable tools to study the process of tumorigenesis. The genetic background of mice carrying a mutation in the murine homolog of the APC gene (ApcMin) is critical to the manifestation of tumor phenotypes, as inbred strains vary in their susceptibility to polyposis. Although complex trait analyses have identified loci tha modify intestinal tumor number and size, mammary tumor development, and radiation-induced adenoma multiplicity in ApcMin/+ mice, less than a handful of genes have been identified to date. It has been suggested that multiple-locus interactions may be one reason that modifier genes are difficult to find. Several genes in a pathway may have to be altered concurrently in order for a shift in phenotype to be detected. We chose to adopt an approach that will account for not only single-locus effects, but phenotypes influenced by multiple-loci inheritance as well. Unlike traditional quantitative trait loci (QTL) studies that exploit the diversity among mouse strains, we will take advantage of genetic similarities between closely-related inbred strains to demonstrate the usefulness of this alternative approach to discover genes that influence tumor phenotypes. We recently found that F1 ApcMin/+ offspring from crosses between C57BL/6J (B6) and closely-related strains have significantly altered susceptibilities to developing polyps than their B6 parents. We will use a combination of classical genetics, molecular tools, and computational resources to identify biomolecular pathways that modulate intestinal tumorigenesis. Our goal is not only to identify new modifier loci, but also to firmly establish thi alternative approach to optimize complex trait screens and speed the process of identification of causative genes influencing susceptibility or resistance to tumorigenesis. PUBLIC HEALTH RELEVANCE: One form of a gene can make a person susceptible to cancer, while another form of the same gene can make another person resistant to a life-threatening cancer. This research is designed to discover genes that function to protect against the development of tumors in the small intestine and colon. A second goal is to establish methods to quickly and efficiently identify these genes and pathways. With this knowledge, research can move towards developing novel preventative options for people at risk and potential therapeutic options for patients with cancer.