The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling.
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.
Tuupanen
Sari
S
Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Turunen
Mikko
M
Lehtonen
Rainer
R
Hallikas
Outi
O
Vanharanta
Sakari
S
Kivioja
Teemu
T
Björklund
Mikael
M
Wei
Gonghong
G
Yan
Jian
J
Niittymäki
Iina
I
Mecklin
Jukka-Pekka
JP
Järvinen
Heikki
H
Ristimäki
Ari
A
Di-Bernardo
Mariachiara
M
East
Phil
P
Carvajal-Carmona
Luis
L
Houlston
Richard S
RS
Tomlinson
Ian
I
Palin
Kimmo
K
Ukkonen
Esko
E
Karhu
Auli
A
Taipale
Jussi
J
Aaltonen
Lauri A
LA
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
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