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Genome Res June 1, 2009; 19 (6): 987-93.

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 .

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.

PubMed ID: 19395656
PMC ID: PMC2694486
Article link: Genome Res
Grant support: [+]

Species referenced: Xenopus
Genes referenced: calr pax4 runx3 smad7 sox17a tgfb1
GO keywords: transcription factor activity, transcription factor binding

Disease Ontology terms: colorectal cancer
References [+] :
Broderick, A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. 2007, Pubmed