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 Ukkonen; Auli Karhu; Jussi Taipale; Lauri A. Aaltonen

doi:10.1038/ng.406

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: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

447 Citations (Scopus)

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 language	English
Pages (from-to)	885-890
Journal	Nature Genetics
Volume	41
Issue number	8
Online published	28 Jun 2009
DOIs	https://doi.org/10.1038/ng.406
Publication status	Published - Aug 2009
Externally published	Yes

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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

@article{a53b502353584d41a7f0baee124ecec3,

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 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. ",

author = "Sari Tuupanen and Mikko Turunen and Rainer Lehtonen and Outi Hallikas and Sakari Vanharanta and Teemu Kivioja and Mikael Bj{\"o}rklund and Gonghong Wei and Jian Yan and Iina Niittym{\"a}ki and Jukka-Pekka Mecklin and Heikki J{\"a}rvinen and Ari Ristim{\"a}ki 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 = aug,

doi = "10.1038/ng.406",

language = "English",

volume = "41",

pages = "885--890",

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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, 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

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 - Björklund, Mikael

AU - Wei, Gonghong

AU - Yan, Jian

AU - Niittymäki, Iina

AU - Mecklin, Jukka-Pekka

AU - Järvinen, Heikki

AU - Ristimäki, 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 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.

AB - 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.

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DO - 10.1038/ng.406

M3 - RGC 21 - Publication in refereed journal

C2 - 19561604

SN - 1061-4036

VL - 41

SP - 885

EP - 890

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

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

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