The genetic lesions that initiate colorectal cancer are relatively well understood. In the overwhelming majority of cases, colorectal cancer cells carry mutations in components of the Wnt signaling pathway (most often in the adenomatous polyposis coli (APC) gene), which confers upon them a marked growth advantage over surrounding normal epithelial cells.^1,2 Although this initial burst in proliferative potential represents an important event in the progression towards adenomas and later carcinomas, clearly other contributing factors must also play their part. Over the years, the classical APCmin/+ model of intestinal tumorigenesis has provided researchers with an excellent tool to test genetically whether candidate genes can enhance or repress adenoma formation in vivo.^3,4 Phenotypically, APCmin mice resemble familial adenomatous polyposis patients, in that they carry inactivating mutations in the APC gene and spontaneously develop numerous polyps along their intestinal tract.⁵

MODIFYING THE MIN PHENOTYPE

The number of APCmin tumours is strongly influenced by the genetic background. On the basis of this observation, linkage studies have identified loci that modify tumour load in APCmin/+ mice, most prominent of which is the secretory phospholipase A2 (Pla2g2a).^6–9 A more effective strategy for identifying modifiers has, however, come through candidate approaches. For a start, several laboratories have looked at the role of genetic surveillance factors such as Mbd4,¹⁰ Myh,¹¹ Fen1¹² and Msh2.¹³ These proteins …