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Genome Research
Year: 2009  |  Volume: 19  |  Issue: 6  |  Page No.: 987 - 993

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

A. M Pittman, S Naranjo, E Webb, P Broderick, E. H Lips, T van Wezel, H Morreau, K Sullivan, S Fielding, P Twiss, J Vijayakrishnan, F Casares, M Qureshi, J. L Gomez Skarmeta and R. S. Houlston    

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; ≥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.

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