A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

Abstract

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-beta and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant (P(trend) = 1.0 x 10(-12)).

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

“…rs7014346 (LRT = 26.64) reached chromosome-wise significance (P < 0.05), further replicating and refining the previous findings 4-6 on the risk locus at 8q24. rs4939827 (LRT = 25.61) is located in intron 3 of SMAD7, replicating a recently reported association between this locus and CRC 7 .…”

“…However, recent association studies have shown that common genetic variation in the 8q24 (refs. [4][5][6] ) and 18q21 (SMAD7) 7 regions also contribute to CRC risk. To explore the role of common genetic variation in CRC etiology, we undertook a comprehensive, phased-design genome-wide association scan (GWAS), capitalizing on Scottish population characteristics.…”

The pursuit of genome-wide association studies: where are we now?

“…One additional gene for colorectal cancer was confirmed other than the 8q24 locus, the SMAD7 gene is involved in TGF-b and Wnt signaling, and abnormalities in these pathways are well established in the pathogenesis of this cancer. [85][86][87] For lung cancer, the first convincing genetic locus also emerged, 15q25, which contained several genes encoding for nicotinic acetylcholine receptors. [88][89][90] The combination of three GWAS further identified additional susceptibility loci for this common cancer, 75 where one of the loci (5p15.33) was also identified by another GWAS.…”

Familial Colorectal Cancer

“…5 Recent results from genome-wide association studies suggest that several different genomic regions may account for a significant proportion of the remainder of the familial risk. [6][7][8] …”

“…5 Recent results from genome-wide association studies suggest that several different genomic regions may account for a significant proportion of the remainder of the familial risk. [6][7][8] Whether a family history of colorectal cancer affects the outcome of patients diagnosed with the disease remains a topic of controversy. A study of 15 369 Japanese patients with a diagnosis of colorectal cancer showed that a family history of the disease was associated with a significantly better outcome.…”