The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.

Abstract	Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.
Authors	Alan M Pittman, Silvia Naranjo, Emily Webb, Peter Broderick, Esther H Lips, Tom van Wezel, Hans Morreau, Kate Sullivan, Sarah Fielding, Philip Twiss, Jayaram Vijayakrishnan, Fernando Casares, Mobshra Qureshi, José Luis Gómez-Skarmeta, Richard S Houlston
Journal	Genome research (Genome Res) Vol. 19 Issue 6 Pg. 987-93 (Jun 2009) ISSN: 1088-9051 [Print] United States
PMID	19395656 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Nuclear Proteins SMAD7 protein, human Smad7 Protein
Topics	Aged Alleles Animals Cell Line, Tumor Chromosome Mapping Chromosomes, Human, Pair 18 (genetics) Colorectal Neoplasms (genetics, pathology) Electrophoretic Mobility Shift Assay Female Gene Expression Gene Frequency Genetic Predisposition to Disease (genetics) Genetic Variation Genotype Humans Male Middle Aged Nuclear Proteins (metabolism) Polymorphism, Single Nucleotide Protein Binding Risk Factors Sequence Analysis, DNA Smad7 Protein (genetics, metabolism) Xenopus laevis (embryology, genetics)

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