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Genetic Polymorphisms and Colorectal Cancer Risk

Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association Studies continued...

It is important to note the limitations of the tagged SNP approach in GWAS in identifying SNPs with minor allele frequencies of 5% to 10%, low-frequency variants with potentially stronger effects, and copy number variants. It is yet unclear how the identification of these new susceptibility alleles in individuals will apply to CRC screening and how comprehensive panels of low-penetrance cancer associated alleles may be applied in the clinical setting.

Genetic Variation in 8q24 andSMAD7

Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with RR ranging from 1.17 to 1.27.[17,18,19] Although the RR is modest for the risk alleles in 8q24, the prevalence (and population-attributable fraction) of these risk alleles is high. The genes responsible for this association have not yet been identified. In addition, common alleles of SMAD7 have also been shown to be associated with an approximately 35% increase in risk of colon cancer.[20]

Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1null allele and the NAT2 G/G allele.[21] None of these alleles has been characterized enough to currently support its routine use in a clinical setting. Family history remains the most valuable tool for establishing risk of colon cancer in these families. Similar to what has been reported in prostate cancer, a combination of susceptibility loci may yet hold promise in profiling individual risk.[22,23]

Variants of Uncertain Significance in Major Cancer Susceptibility Genes


Polymorphisms in APC are the most extensively studied polymorphisms with regard to cancer association. The APC I1307K polymorphism is associated with an increased risk of colon cancer but does not cause colonic polyposis. The I1307K polymorphism occurs almost exclusively in people of Ashkenazi Jewish descent and results in a twofold increased risk of colonic adenomas and adenocarcinomas compared with the general population.[6,24] The I1307K polymorphism results from a transition from T→A at nucleotide 3920 in the APC gene and appears to create a region of hypermutability.[6] Although clinical assays to assess for the APC I1307K polymorphism are currently available, the associated colon cancer risk is not high enough to support routine use. On the basis of currently available data, it is not yet known whether the I1307K carrier state should guide decisions regarding the age to initiate screening, the frequency of screening, or the choice of screening strategy.

Clinical implications of low-penetrance alleles

Although the statistical evidence for an association between genetic variation at these loci and CRC risk is convincing, the biologically relevant variants and the mechanism by which they lead to increased risk are unknown and will require further genetic and functional characterization. Additionally, these loci are associated with very modest risk, with ORs for developing CRC in heterozygous carriers usually from 1.1 to 1.3. More risk variants will likely be identified. Risks in this range do not appear to confer enough increase in age-specific risk as to warrant modification of otherwise clinically prudent screening. Until their collective influence is prospectively evaluated, their use cannot be recommended in clinical practice.


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