Genome-Wide Association Study Points to Colorectal Cancer Culprit

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Several common genetic markers have been found to be associated with colorectal cancer. In a study published online in Genome Research, scientists have now identified a common genetic variation associated with the risk of colorectal cancer and its functional implications, shedding new light on the pathobiology of this disease.

In a genome-wide association study, an international team led by Dr Richard Houlston of The Institute of Cancer Research in the UK have delved into the biology underlying common variants on chromosome 18 that his group recently found to be associated with colorectal cancer. The region of DNA surrounding these markers was sequenced in a large group of colorectal cancer cases and controls, identifying all variants residing in this chromosomal region that were common to colorectal cancer patients.

Houlston et al then focused on the novel variant most strongly associated with colorectal cancer, and found that it resides within a DNA sequence that is conserved in many other species—so well conserved that they were able to use Xenopus laevis as a model organism to test the biological consequences of this single nucleotide polymorphism (SNP). The group found that the SNP reduces expression of a nearby gene, SMAD7, a negative regulator of transforming growth factor (TGF)-β signaling. If cellular levels of SMAD7 are reduced, critical signaling events could be set into motion, leading to carcinogenesis. Disruption of SMAD7 expression has previously been implicated in progression of colorectal cancer.

The authors conclude that, when viewed within the context of previous findings, their observation supports a direct role for SMAD7 in cancer progression, and very likely represents the causal basis for colorectal cancer risk associated with this chromosomal region. “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-β signaling,” they state.

See “The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression,” Genome Research, advanced online edition, April 24, 2009.