Article abstract
Nature Genetics 41, 885 - 890 (2009)
Published online: 28 June 2009 | doi:10.1038/ng.406
The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling
Sari Tuupanen1, Mikko Turunen2,3, Rainer Lehtonen1, Outi Hallikas2,3, Sakari Vanharanta1,12, Teemu Kivioja2,4, Mikael Björklund2,3, Gonghong Wei2,3, Jian Yan2,3, Iina Niittymäki1, Jukka-Pekka Mecklin5, Heikki Järvinen6, Ari Ristimäki7,9, Mariachiara Di-Bernardo10, Phil East11, Luis Carvajal-Carmona11, Richard S Houlston10, Ian Tomlinson11, Kimmo Palin4,12, Esko Ukkonen4, Auli Karhu1, Jussi Taipale2,3 & Lauri A Aaltonen1
Abstract
Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk 
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.
- Department of Medical Genetics, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
- Institute of Biomedicine, Genome-Scale Biology Research Program, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
- Department of Molecular Medicine, National Public Health Institute, University of Helsinki, Helsinki, Finland.
- Department of Computer Science, University of Helsinki, Helsinki, Finland.
- Department of Surgery, Jyväskylä Central Hospital, Jyväskylä, Finland.
- The Second Department of Surgery, Helsinki University Hospital, Helsinki, Finland.
- Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland.
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital, Helsinki, Finland.
- Department of Pathology, University of Oulu and Oulu University Hospital, Oulu, Finland.
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.
- Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Headington, Oxford, UK.
- Present addresses: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA (S.V.) and Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK (K.P.).
Correspondence to: e-mail: lauri.aaltonen@helsinki.fi
Correspondence to: Jussi Taipale2,3Lauri A Aaltonen1 e-mail: jussi.taipale@helsinki.fi
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