title: Mice lacking a Myc enhancer that includes human SNP rs6983267 are resistant to intestinal tumors.
abstract: Multiple cancer-associated single-nucleotide polymorphisms (SNPs) have been mapped to conserved sequences within a 500-kilobase region upstream of the MYC oncogene on human chromosome 8q24. These SNPs may affect cancer development through altered regulation of MYC expression, but this hypothesis has been difficult to confirm. 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 establish that a cancer-associated SNP identified in human genome-wide association studies has a functional effect in vivo.
authors.affiliation: Science for Life Center, Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Inderpreet Kaur
authors.initials: IK
authors.lastname: Sur
authors.forename: Outi
authors.initials: O
authors.lastname: Hallikas
authors.forename: Anna
authors.initials: A
authors.lastname: Vähärautio
authors.forename: Jian
authors.initials: J
authors.lastname: Yan
authors.forename: Mikko
authors.initials: M
authors.lastname: Turunen
authors.forename: Martin
authors.initials: M
authors.lastname: Enge
authors.forename: Minna
authors.initials: M
authors.lastname: Taipale
authors.forename: Auli
authors.initials: A
authors.lastname: Karhu
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Jussi
authors.initials: J
authors.lastname: Taipale
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000235:genetics / Q000473:pathology; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D003106:Colon / Q000378:metabolism / Q000473:pathology; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D020641:Polymorphism, Single Nucleotide; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*
chemical_list: D016271:Proto-Oncogene Proteins c-myc