Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice

Apc(Min) mice have provided an example of a locus (Modifier of Min1; Mom1) modifying adenoma numbers in the intestines of inbred strains. Linkage analysis located Mom1 on chromosome 4, and further investigation identified secretory phospholipase A2 (Pla2g2a) as a candidate gene. Because of unknown variation introduced by a single founding male mouse, our Min stock, although Pla2g2a(Mom1-s), was not on a pure C57BL/6J background and exhibited several polymorphic loci, including a region on chromosome 18 distal to Apc. Through selective breeding for homozygosity for distal chromosome 18 markers, six recombinant lines that presented with limited intraline variation in adenoma numbers were established. One line (V) showed a particularly severe phenotype (mean adenoma number +/- SEM, 370 +/- 21) compared with the other lines that recorded significantly lower means (3- to 5-fold; P < 10(-3), t test). Intercrosses between lines I and V showed suppression of the severe phenotype in the N1 generation. In N2 (and subsequent) backcrosses, tumor multiplicity depended on the origins of the WT and Min Apc alleles. Mice carrying both alleles from line V had a severe phenotype; others had mild disease very similar to line I (likelihood ratio statistic > 49.0; likelihood of odds > 10; P < 10(-5)). Frequency of allele loss at Apc was increased significantly in adenomas of mice with more severe disease. We propose that a modifier gene close to Apc or structural variation on chromosome 18 modifies polyp numbers in our mice, possibly by altering the frequency of WT Apc allele loss.