Journal Article

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

Wei, Gonghong, Carvajal-Carmona, Luis, Yan, Jian, Järvinen, Heikki, Palin, Kimmo, Houlston, Richard S, Aaltonen, Lauri A, Tomlinson, Ian, Tuupanen, Sari, Kivioja, Teemu, Mecklin, Jukka-Pekka, Taipale, Jussi, Hallikas, Outi, Ristimäki, Ari, Ukkonen, Esko, Karhu, Auli, Lehtonen, Rainer, Turunen, Mikko, Niittymäki, Iina, Di-Bernardo, Mariachiara, Vanharanta, Sakari, East, Phil, Björklund, Mikael

2009

Overview

Lauri Aaltonen and colleagues show that a region on 8q24 associated with colorectal cancer risk functions as an enhancer and that the risk allele at this locus binds with higher affinity to the Wnt-regulated transcription factor TCF4 (also called TCF7L2), conferring enhanced responsiveness to Wnt signaling. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: Agriculture / Animal Genetics and Genomics / Animals / Base Sequence / beta Catenin - metabolism / Binding Sites / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Cancer Research / Cancer therapies / Cell physiology / Chromosomes / Chromosomes, Human, Pair 8 - genetics / Classical genetics, quantitative genetics, hybrids / Colorectal cancer / Colorectal carcinoma / Colorectal Neoplasms - genetics / Conserved Sequence / Disease susceptibility / Embryo, Mammalian - metabolism / Enhancer Elements, Genetic - genetics / Fundamental and applied biological sciences. Psychology / Gastroenterology. Liver. Pancreas. Abdomen / Gene Dosage / Gene expression / Gene Function / Genetic aspects / Genetic Predisposition to Disease / Genetics / Genetics of eukaryotes. Biological and molecular evolution / Genome-Wide Association Study / Health aspects / Homozygosity / Human Genetics / Humans / Medical sciences / Methods / Methods, theories and miscellaneous / Mice / Mice, Transgenic / Molecular and cellular biology / Molecular Sequence Data / Organ Specificity / Polymorphism, Single Nucleotide - genetics / Protein Binding / Proto-Oncogene Proteins c-myc - metabolism / Reproducibility of Results / Risk factors / Signal Transduction / Single nucleotide polymorphisms / Stomach. Duodenum. Small intestine. Colon. Rectum. Anus / Studies / TCF Transcription Factors - metabolism / Transcription Factor 7-Like 2 Protein / Tumors / Wnt Proteins - metabolism