The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression
- Alan M. Pittman1,
- Silvia Naranjo2,
- Emily Webb1,
- Peter Broderick1,
- Esther H. Lips3,
- Tom van Wezel3,
- Hans Morreau3,
- Kate Sullivan1,
- Sarah Fielding1,
- Philip Twiss1,
- Jayaram Vijayakrishnan1,
- Fernando Casares2,
- Mobshra Qureshi1,
- José Luis Gómez-Skarmeta2 and
- Richard S. Houlston1,4
- 1 Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom;
- 2 Centro Andaluz de Biología del Desarrollo, CSIC-UPO, Carretera de Utrera Km1, 41013 Seville, Spain;
- 3 Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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 × 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.
Footnotes
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↵4 Corresponding author.
E-mail Richard.houlston{at}icr.ac.uk; fax +44-0208-722-4365.
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[Supplemental material is available online at www.genome.org.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.092668.109.
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- Received February 11, 2009.
- Accepted March 16, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press
