GENETIC MODIFIERS OF COLORECTAL TUMORIGENESIS

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The study of genes that influence career susceptibility is a rapidly evolving field. The power of mouse genetics coupled with the ability to scan entire genomes of individual animals has led to the discovery that several chromosomal regions harbor genes conferring susceptibility or resistance to different types of cancers. This proposal is focused on identifying and characterizing genes that influence the development of cancers in the gastrointestinal tract. Our goals are two-fold: 1) to further investigated the first candidate gene identified for a quantitative trait locus (QTL), and 2) to use newly established mutant and congenic mouse lines to identify additional chromosomal regions that harbor genes influencing career susceptibility. The system we have chosen involves the tumor suppressor gene Adenomatous Polyposis Coli (APC). Mutations in APC cause inherited and sporadic colorectal cancers. Apc/Min mice have a mutation in the homologue of the APC genome and develop multiple adenomas throughout their small and large intestines. QTL studies identified a locus, Modifier of Min (Mom1), which maps to the distal region of chromosome 4. The MOM1 locus dramatically modifies Apc/Min-induced tumor number. We previously reported that the secretory type II Phospholipase A2 (PLA2g2a) gene is a strong candidate for the Mm1 locus. Inbred strains of mice display 100% concordance between Pla2g2a allele type and tumor susceptibility. Expression and sequence analysis revealed that Mom1 susceptible strains are null for Pla2g2a activity. We propose to examine further the Pla2g2a gene and its effects in both mouse and human tumors. In addition, we have discovered a spontaneous mutation (Mom2) that appears to be a potent suppressor of tumorigenesis in Apc/Min mice. We propose to refine the map location pf the Mom2 locus and investigate candidate genes. Finally, we have established mice congenic for Pla2q2a-/- on an otherwise resistant inbred strain background. Using this new congenic strain in designated crosses, we will analyze offspring for tumor number and QTL analyses to identify additional regions of the genome that can influence polyp formation. The further examination of both PLA2G2A and newly identified modifier loci in human tumors should allow an understanding of the relationship between the effects of modifier genes on tumor formation and progression. Further investigations will ultimately lead to insights regarding the predictive value of these modifier genes in tumor prevention and response to treatment.