title: The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling.
abstract: Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk approximately 1.5 fold. We report here that the risk allele G shows copy number increase during CRC development. Our computer algorithm, Enhancer Element Locator (EEL), identified an enhancer element that contains rs6983267. The element drove expression of a reporter gene in a pattern that is consistent with regulation by the key CRC pathway Wnt. rs6983267 affects a binding site for the Wnt-regulated transcription factor TCF4, with the risk allele G showing stronger binding in vitro and in vivo. Genome-wide ChIP assay revealed the element as the strongest TCF4 binding site within 1 Mb of MYC. An unambiguous correlation between rs6983267 genotype and MYC expression was not detected, and additional work is required to scrutinize all possible targets of the enhancer. Our work provides evidence that the common CRC predisposition associated with 8q24 arises from enhanced responsiveness to Wnt signaling.
authors: Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors: Sari
authors: S
authors: Tuupanen
authors: Mikko
authors: M
authors: Turunen
authors: Rainer
authors: R
authors: Lehtonen
authors: Outi
authors: O
authors: Hallikas
authors: Sakari
authors: S
authors: Vanharanta
authors: Teemu
authors: T
authors: Kivioja
authors: Mikael
authors: M
authors: Björklund
authors: Gonghong
authors: G
authors: Wei
authors: Jian
authors: J
authors: Yan
authors: Iina
authors: I
authors: Niittymäki
authors: Jukka-Pekka
authors: JP
authors: Mecklin
authors: Heikki
authors: H
authors: Järvinen
authors: Ari
authors: A
authors: Ristimäki
authors: Mariachiara
authors: M
authors: Di-Bernardo
authors: Phil
authors: P
authors: East
authors: Luis
authors: L
authors: Carvajal-Carmona
authors: Richard S
authors: RS
authors: Houlston
authors: Ian
authors: I
authors: Tomlinson
authors: Kimmo
authors: K
authors: Palin
authors: Esko
authors: E
authors: Ukkonen
authors: Auli
authors: A
authors: Karhu
authors: Jussi
authors: J
authors: Taipale
authors: Lauri A
authors: LA
authors: Aaltonen
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics*; D017124:Conserved Sequence; D004622:Embryo, Mammalian / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016271:Proto-Oncogene Proteins c-myc; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D051176:beta Catenin