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

Sari Tuupanen, Mikko Turunen, Rainer Lehtonen, Outi Hallikas, Sakari Vanharanta, Teemu Kivioja, Mikael Björklund, Gonghong Wei, Jian Yan, Iina Niittymäki, Jukka Pekka Mecklin, Heikki Järvinen, Ari Ristimäki, Mariachiara Di-Bernardo, Phil East, Luis Carvajal-Carmona, Richard S. Houlston, Ian Tomlinson, Kimmo Palin, Esko UkkonenAuli Karhu, Jussi Taipale, Lauri A. Aaltonen

Research output: Contribution to journalArticle

383 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)885-890
Number of pages6
JournalNature Genetics
Volume41
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

ASJC Scopus subject areas

  • Genetics

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    Tuupanen, S., Turunen, M., Lehtonen, R., Hallikas, O., Vanharanta, S., Kivioja, T., Björklund, M., Wei, G., Yan, J., Niittymäki, I., Mecklin, J. P., Järvinen, H., Ristimäki, A., Di-Bernardo, M., East, P., Carvajal-Carmona, L., Houlston, R. S., Tomlinson, I., Palin, K., ... Aaltonen, L. A. (2009). The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nature Genetics, 41(8), 885-890. https://doi.org/10.1038/ng.406