The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.
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.
Pittman
Alan M
AM
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey SM2 5NG, United Kingdom.
Naranjo
Silvia
S
Webb
Emily
E
Broderick
Peter
P
Lips
Esther H
EH
van Wezel
Tom
T
Morreau
Hans
H
Sullivan
Kate
K
Fielding
Sarah
S
Twiss
Philip
P
Vijayakrishnan
Jayaram
J
Casares
Fernando
F
Qureshi
Mobshra
M
Gómez-Skarmeta
José Luis
JL
Houlston
Richard S
RS
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
D009687:Nuclear Proteins; C497806:SMAD7 protein, human; D051906:Smad7 Protein