Secretory phospholipase A2: A candidate for the MOM1 locus, a major modifier of APC(Min)-induced intestinal neoplasia
Mutations in the Adenomatous Polyposis Coli (APC) gene are responsible for various familial and sporadic colorectal cancers. Min (Multiple intestinal neoplasia) mice carry a dominant mutation in the murine homolog of the Apc gene. Min mice develop multiple adenomas throughout their small and large intestine. Recent studies have identified a modifier locus, Mom1, which maps to the distal region of chromosome 4. Mom1 dramatically influences Min-induced tumor number. We report here the identification of a candidate gene for Mom1. The gene for secretory type II Phospholipase A2 (Pla2g2a) maps between D4Mit16 and D4Mit13 on the distal region of chromosome 4, the same region that contains Mom1, and displays 100% concordance between allele type and tumor susceptibility. Expression, sequencing and protein analysis revealed that Mom1 susceptible strains have a null allele for Pla2g2a and most likely lack any Pla2g2a activity. Our results suggest that Pla2g2a acts as a novel gene which modifies polyp number by altering the cellular microenvironment within the intestinal crypt.