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 Bjorklund, Gonghong Wei, Jian Yan, Iina Niittymaki, Jukka-Pekka Mecklin, Heikki Jarvinen, Ari Ristimaki, 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

    384 Citations (Scopus)

    Abstract

    Homozygosity for the G allele of rs6983267 at 8q24 increases colorectal cancer (CRC) risk B1.5 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
    Pages (from-to)885-890
    Number of pages6
    JournalNature Genetics
    Volume41
    Issue number8
    DOIs
    Publication statusPublished - Aug 2009

    Keywords

    • Genome-wide association
    • Beta-catenin
    • Prostate cancer
    • Susceptibility locus
    • Genetic variation
    • Colon cancer
    • Risk
    • Elements
    • Variants
    • Scan

    Cite this