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PMID: 19561604 Published · ppublish English Journal Article

The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling.

Nature genetics ·Vol. 41 ·No. 8 ·2009-08-00 ·Pages 885-90

Tuupanen S, Turunen M, Lehtonen R, Hallikas O, Vanharanta S, Kivioja T, Björklund M, Wei G, Yan J, Niittymäki I, Mecklin JP, Järvinen H, Ristimäki A, Di-Bernardo M, East P, Carvajal-Carmona L, Houlston RS, Tomlinson I, Palin K, Ukkonen E, Karhu A, Taipale J, Aaltonen LA

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.

MeSH Terms
Animals Base Sequence Binding Sites Chromosomes, Human, Pair 8/genetics Colorectal Neoplasms/genetics Conserved Sequence Embryo, Mammalian/metabolism Enhancer Elements, Genetic/genetics Gene Dosage Genetic Predisposition to Disease Genome-Wide Association Study Humans Mice Mice, Transgenic Molecular Sequence Data Organ Specificity Polymorphism, Single Nucleotide/genetics Protein Binding Proto-Oncogene Proteins c-myc/metabolism Reproducibility of Results Signal Transduction TCF Transcription Factors/metabolism Transcription Factor 7-Like 2 Protein Wnt Proteins/metabolism beta Catenin/metabolism
Chemicals
Proto-Oncogene Proteins c-myc TCF Transcription Factors TCF7L2 protein, human Tcf7l2 protein, mouse Transcription Factor 7-Like 2 Protein Wnt Proteins beta Catenin
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Tuupanen Sari
Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
Turunen Mikko
Lehtonen Rainer
Hallikas Outi
Vanharanta Sakari
Kivioja Teemu
Björklund Mikael
Wei Gonghong
Yan Jian
Niittymäki Iina
Mecklin Jukka-Pekka
Järvinen Heikki
Ristimäki Ari
Di-Bernardo Mariachiara
East Phil
Carvajal-Carmona Luis
Houlston Richard S
Tomlinson Ian
Palin Kimmo
Ukkonen Esko
Karhu Auli
Taipale Jussi
Aaltonen Lauri A
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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.406
Published
2009-08-00
Epub
2009-00-28
Pages
885-90
Language
English
Region
United States
NLM ID
9216904
Subset
IM
Corrections
CommentIn
PMID: 19639026
External Links
PubMed source DOI: 10.1038/ng.406 View journal details
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