In this work, we generated mice deficient in Myc-335, a putative MYC regulatory element that contains rs6983267, a SNP accounting for more human cancer-related morbidity than any other genetic variant or mutation. In Myc-335 null mice, Myc transcripts were expressed in the intestinal crypts in a pattern similar to that in wild-type mice but at modestly reduced levels. The mutant mice displayed no overt phenotype but were markedly resistant to intestinal tumorigenesis induced by the APCmin mutation. These results highlight the fact that although a disease-associated polymorphism typically has a relatively modest effect size, the element that it affects can be critically important for the underlying pathological process. The finding also indicates that normal growth control and pathological growth induced by cancer can utilize different mechanisms.
