Secretory phospholipase Pla2g2a confers resistance to intestinal tumorigenesis

Abstract

Individuals inheriting the same mutation predisposing to cancer may show very different outcomes, ranging from early aggressive cancer to disease–free survival. Experimental mouse models can provide a powerful tool to identify factors in the environment and genetic background that account for such modifications. The Min mouse strain1, in which the Apc^Min mutation disrupts the mouse homologue of the human familial polyposis gene², develops intestinal neoplasms whose multiplicity is strongly affected by genetic background³. We previously mapped^4,5 a strong modifier locus, Mom1 (modifier of Min–1), to a 4–cM region on mouse chromosome 4 containing a candidate gene Pla2g2a encoding a secretory phospholipase⁶. Here, we report that a cosmid transgene overexpressing Pla2g2a caused a reduction in tumour multiplicity and size, comparable to that conferred by a single copy of the resistance allele of Mom1. These results offer strong evidence that this secretory phospholipase can provide active tumour resistance. The association of Pla2g2a with Mom1 thus withstands a strong functional test and is likely to represent the successful identification of a polymorphic quantitative trait locus in mammals.