Colon Cancer Risk: More Evidence for Common Disease, Common Gene Hypothesis

We know from both population-based epidemiologic studies and from twin studies that our genes make a substantial contribution to risk for colorectal (aka colon) cancer.  Although there are several relatively uncommon familial colon cancer predisposition syndromes (which account for <5% of all colon cancer) with known genes involved, progress towards unraveling genomic variants involved in the more common, run-of-the-mill colon cancer cases has been slower in coming. 

However, a study published recently in the journal Nature Genetics reports significant progress in this regard.  This study is one of a flurry of genome-wide association studies (GWAS) - which utilize a study design made possible by recent advances in our ability to simultaneously examine an individual's genotype at hundreds of thousands of sites of single nucleotide polymorphisms (SNPs).

Pursuing the idea that variation in colon cancer risk may be due to relatively common low risk SNPs (perhaps in combination), many of the same authors (a group led by Richard Houlston and Ian Tomlinson) had reported in the August 2007 Nature Genetics that a SNP located on chromosome 8 was associated with colon cancer.  Although statistical support was strong, it is important to keep in mind that the risk to individuals with the variant SNP (whether they have one copy or two) was modest.  Odds ratios were 1.27 for heterozygotes (with one copy of the risk variant) and 1.47 for homozygotes (who carry the risk variant on both copies of chromosome 8).  There were also reports from other groups in Nature Genetics about colon cancer risk and this region of chromosome 8. 

Now, in the new paper published online in the November 2007 issue of Nature Genetics, the group led by Houlston and Tomlinson focused on another strong signal from their genome-wide association study.  They identified three SNPs in a gene called SMAD7 that were very significantly associated with colon cancer risk.  Interestingly, as with the results from a number of other recent GWAS studies, the significant SNPs were intronic (i.e., located in an intron, in between the exons which are the stretches of DNA with the information coding for amino acids, the protein building blocks).  As is often the case, the functional SNP at this locus is unknown at this point. 

SMAD7 is also known as "mothers against decapentaplegic homolog 7."  Unfortunately for those of us who have to deal with this stuff clinically, the drosophila (fruitfly) genetics community has a tradition of picking names of this sort.  Nevertheless, the available information about SMAD7 function within the cell suggests that it is quite plausible as a colon cancer risk gene.  Specifically, it acts as an antagonist of TGF-beta signalling, a pathway known to be relevant to colon cancer development.   

The authors suggest that the SMAD7 risk variants likely contribute to about 15% of colorectal cancer cases.  For those of us practicing clinical cancer genetics, however, it is important to note that SMAD7 seems to be involved in less than 1% of familial colon cancer though.  This fact, in conjunction with the relatively modest odds ratios, will likely limit applicability of this new result to the individual patient.  Nevertheless, I can certainly see a future coming in which the SMAD7 SNPs - presumably in conjunction with other colon cancer risk SNPs - are utilized on a population-wide basis to partition individuals into different risk categories with different recommended screening strategies.