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

Authors:Pittman, Alan M.
Naranjo, Silvia
Webb, Emily
Broderick, Peter
Lips, Esther H.
Van Wezel, Tom
Morreau, Hans
Sullivan, Kate
Fielding, Sarah
Twiss, Philip
Vijayakrishnan, Jayaram
Casares, Fernando
Qureshi, Mobshra
Gómez-Skarmeta, José Luis
Houlston, Richard S.
Keywords:Colorectal cancer (CRC), 18q21 variation, SMAD7 expression, TGF-beta signaling
Issue Date:24-Apr-2009
Publisher:Cold Spring Harbor Laboratory. Press
Citation:Genome Research 19(6): 987-993 (2009)
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 × 10−7; ≥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 × 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.
Description:7 páginas, 4 figuras, 1 tabla.
Publisher version (URL):http://dx.doi.org/10.1101/gr.092668.109
URI:http://hdl.handle.net/10261/12559
ISSN:1088-9051
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Appears in Collections:(CABD) Artículos

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