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; (2009) The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression. Genome research, 19 (6). pp. 987-93. ISSN 1088-9051 DOI: https://doi.org/10.1101/gr.092668.109

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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); > 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.

Item Type: Article
Faculty and Department: Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
PubMed ID: 19395656
Web of Science ID: 266521500004
URI: http://researchonline.lshtm.ac.uk/id/eprint/2451

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