title: The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.
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.
authors.affiliation: Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Pittman
authors.forename: Silvia
authors.initials: S
authors.lastname: Naranjo
authors.forename: Emily
authors.initials: E
authors.lastname: Webb
authors.forename: Peter
authors.initials: P
authors.lastname: Broderick
authors.forename: Esther H
authors.initials: EH
authors.lastname: Lips
authors.forename: Tom
authors.initials: T
authors.lastname: van Wezel
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Kate
authors.initials: K
authors.lastname: Sullivan
authors.forename: Sarah
authors.initials: S
authors.lastname: Fielding
authors.forename: Philip
authors.initials: P
authors.lastname: Twiss
authors.forename: Jayaram
authors.initials: J
authors.lastname: Vijayakrishnan
authors.forename: Fernando
authors.initials: F
authors.lastname: Casares
authors.forename: Mobshra
authors.initials: M
authors.lastname: Qureshi
authors.forename: José Luis
authors.initials: JL
authors.lastname: Gómez-Skarmeta
authors.forename: Richard S
authors.initials: RS
authors.lastname: Houlston
mesh_terms: D000368:Aged; D000483:Alleles; D000818:Animals; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics
chemical_list: D009687:Nuclear Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein