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Título : The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression
Autor : Pittman, Alan M., Naranjo, Silvia, Webb, Emily, Broderick, Peter, Lips, Esther H., Van Wezel, Tom, Morreau, Hans, Sullivan, Kate, Fielding, Sarah, Twiss, Philip, Vijayakrishnan, Jayaram, Casares, Fernando, Qureshi, Mobshra, Gómez-Skarmeta, José Luis, Houlston, Richard S.
Palabras clave : Colorectal cancer (CRC)
18q21 variation
SMAD7 expression
TGF-beta signaling
Fecha de publicación : 24-Apr-2009
Editor: Cold Spring Harbor Laboratory. Press
Resumen: 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.
Descripción : 7 páginas, 4 figuras, 1 tabla.
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ISSN: 1088-9051
DOI: 10.1101/gr.092668.109
Citación : Genome Research 19(6): 987-993 (2009)
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