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 Ukkonen & 3 others Auli Karhu, Jussi Taipale, Lauri A. Aaltonen

    Research output: Contribution to journalArticle

    367 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

    Tuupanen, S., Turunen, M., Lehtonen, R., Hallikas, O., Vanharanta, S., Kivioja, T., ... 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
    Tuupanen, Sari ; Turunen, Mikko ; Lehtonen, Rainer ; Hallikas, Outi ; Vanharanta, Sakari ; Kivioja, Teemu ; Bjorklund, Mikael ; Wei, Gonghong ; Yan, Jian ; Niittymaki, Iina ; Mecklin, Jukka-Pekka ; Jarvinen, Heikki ; Ristimaki, 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. / The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. In: Nature Genetics. 2009 ; Vol. 41, No. 8. pp. 885-890.
    @article{ef79d5af4f6a420596ae96edaeb7ab22,
    title = "The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling",
    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.",
    keywords = "Genome-wide association , Beta-catenin, Prostate cancer, Susceptibility locus, Genetic variation, Colon cancer, Risk, Elements, Variants, Scan",
    author = "Sari Tuupanen and Mikko Turunen and Rainer Lehtonen and Outi Hallikas and Sakari Vanharanta and Teemu Kivioja and Mikael Bjorklund and Gonghong Wei and Jian Yan and Iina Niittymaki and Jukka-Pekka Mecklin and Heikki Jarvinen and Ari Ristimaki and Mariachiara Di-Bernardo and Phil East and Luis Carvajal-Carmona and Houlston, {Richard S.} and Ian Tomlinson and Kimmo Palin and Esko Ukkonen and Auli Karhu and Jussi Taipale and Aaltonen, {Lauri A.}",
    year = "2009",
    month = "8",
    doi = "10.1038/ng.406",
    language = "English",
    volume = "41",
    pages = "885--890",
    journal = "Nature Genetics",
    issn = "1061-4036",
    publisher = "Nature Publishing Group",
    number = "8",

    }

    Tuupanen, S, Turunen, M, Lehtonen, R, Hallikas, O, Vanharanta, S, Kivioja, T, Bjorklund, M, Wei, G, Yan, J, Niittymaki, I, Mecklin, J-P, Jarvinen, H, Ristimaki, A, Di-Bernardo, M, East, P, Carvajal-Carmona, L, Houlston, RS, Tomlinson, I, Palin, K, Ukkonen, E, Karhu, A, Taipale, J & Aaltonen, LA 2009, 'The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling', Nature Genetics, vol. 41, no. 8, pp. 885-890. https://doi.org/10.1038/ng.406

    The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. / Tuupanen, Sari; Turunen, Mikko; Lehtonen, Rainer; Hallikas, Outi; Vanharanta, Sakari; Kivioja, Teemu; Bjorklund, Mikael; Wei, Gonghong; Yan, Jian; Niittymaki, Iina; Mecklin, Jukka-Pekka; Jarvinen, Heikki; Ristimaki, 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.

    In: Nature Genetics, Vol. 41, No. 8, 08.2009, p. 885-890.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling

    AU - Tuupanen, Sari

    AU - Turunen, Mikko

    AU - Lehtonen, Rainer

    AU - Hallikas, Outi

    AU - Vanharanta, Sakari

    AU - Kivioja, Teemu

    AU - Bjorklund, Mikael

    AU - Wei, Gonghong

    AU - Yan, Jian

    AU - Niittymaki, Iina

    AU - Mecklin, Jukka-Pekka

    AU - Jarvinen, Heikki

    AU - Ristimaki, Ari

    AU - Di-Bernardo, Mariachiara

    AU - East, Phil

    AU - Carvajal-Carmona, Luis

    AU - Houlston, Richard S.

    AU - Tomlinson, Ian

    AU - Palin, Kimmo

    AU - Ukkonen, Esko

    AU - Karhu, Auli

    AU - Taipale, Jussi

    AU - Aaltonen, Lauri A.

    PY - 2009/8

    Y1 - 2009/8

    N2 - 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.

    AB - 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.

    KW - Genome-wide association

    KW - Beta-catenin

    KW - Prostate cancer

    KW - Susceptibility locus

    KW - Genetic variation

    KW - Colon cancer

    KW - Risk

    KW - Elements

    KW - Variants

    KW - Scan

    U2 - 10.1038/ng.406

    DO - 10.1038/ng.406

    M3 - Article

    VL - 41

    SP - 885

    EP - 890

    JO - Nature Genetics

    JF - Nature Genetics

    SN - 1061-4036

    IS - 8

    ER -