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; 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 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 journal › Article › peer-review

438 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 language	English
Pages (from-to)	885-890
Number of pages	6
Journal	Nature Genetics
Volume	41
Issue number	8
DOIs	https://doi.org/10.1038/ng.406
Publication status	Published - Aug 2009

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/ng.406

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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, 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{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 = aug,

doi = "10.1038/ng.406",

language = "English",

volume = "41",

pages = "885--890",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

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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

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

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

Abstract

Keywords

UN SDGs

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