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Genome Res
2009 Jun 01;196:987-93. doi: 10.1101/gr.092668.109.
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The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.
Pittman AM
,
Naranjo S
,
Webb E
,
Broderick P
,
Lips EH
,
van Wezel T
,
Morreau H
,
Sullivan K
,
Fielding S
,
Twiss P
,
Vijayakrishnan J
,
Casares F
,
Qureshi M
,
Gómez-Skarmeta JL
,
Houlston RS
.
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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.
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19395656
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