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The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling
- Source :
- Nature Genetics
- Publication Year :
- 2009
-
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.
- Subjects :
- Beta-catenin
Molecular Sequence Data
Gene Dosage
Genome-wide association study
Mice, Transgenic
TCF/LEF family
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Mice
0302 clinical medicine
Genetics
Animals
Humans
Genetic Predisposition to Disease
Allele
Enhancer
Transcription factor
Conserved Sequence
beta Catenin
030304 developmental biology
0303 health sciences
Binding Sites
biology
Base Sequence
Wnt signaling pathway
Reproducibility of Results
TCF4
Embryo, Mammalian
Wnt Proteins
Enhancer Elements, Genetic
Organ Specificity
030220 oncology & carcinogenesis
biology.protein
Colorectal Neoplasms
TCF Transcription Factors
Transcription Factor 7-Like 2 Protein
Chromosomes, Human, Pair 8
Genome-Wide Association Study
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 15461718
- Volume :
- 41
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Nature genetics
- Accession number :
- edsair.doi.dedup.....8ce35c19add417da40115eb1815b1167