RT Journal
A1 Pittman, Alan M.
A1 Naranjo, Silvia
A1 Webb, Emily
A1 Broderick, Peter
A1 Lips, Esther H.
A1 van Wezel, Tom
A1 Morreau, Hans
A1 Sullivan, Kate
A1 Fielding, Sarah
A1 Twiss, Philip
A1 Vijayakrishnan, Jayaram
A1 Casares, Fernando
A1 Qureshi, Mobshra
A1 Gómez-Skarmeta, José Luis
A1 Houlston, Richard S.
T1 The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression
JF Genome Research 
JO Genome Research 
YR 2009 
FD June 01 
VO 19 
IS 6 
SP 987 
OP 993 
DO 10.1101/gr.092668.109 
UL http://genome.cshlp.org/content/19/6/987.abstract 
AB 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.