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Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/12559
Title: 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
DOI: 10.1101/gr.092668.109
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