Further genetic analysis of the Mom1 locus

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DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is one of the major malignancies in the United States, accounting for 130,000 new cases and more than 50,000 deaths each year. Notably, the incidence and mortality rates from CRC have remained fairly constant over the past three decades despite advances in early detection and therapy. To develop effective prevention and therapeutic modalities for CRC an emergent challenge for cancer investigators is to identify and characterize the constellation of genetic factors that underlie CRC susceptibility. Key research tools are genetically defined mouse models such as the ApcMin/+ mouse. The principal investigator for this application and others have used the sensitized Min mouse to map the Mom 1 locus, a complex of genes on mouse chromosome four that confers significant resistance to Min-induced tumorigenesis. We have functionally cloned one gene in this complex, the secretory phospholipase Pla2g2a, which lies in the proximal region of Mom1. The distal modifier gene(s) of Mom1 lie in a region of approximately 8 MB. This proposal extends our previous work by creating a new panel of recombinant congenic mouse lines that will be used to map the distal modifier gene at high resolution, followed by its positional cloning. A second aim of this proposal is to expand upon our previous transgenic studies of Pla2g2a by creating a targeted replacement "knockin" of a wildtype copy of Pla2g2a (derived from the AKR strain) into the naturally mutant C57BL/6 genetic background. There is some evidence that the mutant B6 Pla2g2a protein retains catalytic-independent function, thus, wildtype replacement of the endogenous mutant genes on the tumor-robust B6 genetic background should provide a better understanding of Pla2g2a's role in tumor resistance as expression of wildtype Pla2g2a will now occur in the absence of endogenous mutant B6 Pla2g2a.