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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U2 - 10.1038/ng.406
DO - 10.1038/ng.406
M3 - Article
C2 - 19561604
AN - SCOPUS:68149170044
VL - 41
SP - 885
EP - 890
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 8
ER -