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Genetics of Colorectal Cancer (PDQ®): Genetics - Health Professional Information [NCI] - Genetic Polymorphisms and Colorectal Cancer Risk

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

Polymorphisms in Unrelated Genes Affecting Expression in LS

Polymorphisms potentially affecting expression in MMR genes fall into two categories: those whose mechanisms are already suspected to have an effect on cancer-related pathways, and those that are truly anonymous. Several candidate genes have been studied. Anonymous genes have also been evaluated.

Studies have demonstrated that a polymorphism in the promoter region of the insulin-like growth factor 1 (IGF1) gene modifies age of onset of CRC in LS.[25,26]. The polymorphism is a variable number of CA-dinucleotide repeats approximately 1 kb upstream of the transcription start site of IGF1. There is significant variability between individuals and populations with respect to repeat length. Carriers of shorter repeat lengths (shortest allele ≤17 repeats) develop CRC on average 12 years earlier than those with longer repeat lengths. It is unclear what influence this polymorphism may have on extracolonic malignancies. Additionally, the cyclin D1 polymorphism G870A may be associated with earlier age of onset of CRC in LS,[27,28] although the association appears to be more reproducible in MSH2 mutation carriers than in MLH1 mutation carriers.[28,29]

Two SNPs identified in GWAS have been reported to increase CRC risk in MMR gene mutation carriers. (Refer to the Genome-wide searches section of this summary for more information.) Having the C-allele of either SNP increased the risk of CRC in a dose-dependent fashion (with homozygotes at a higher risk than heterozygotes). The first SNP in 8q23.3 increased CRC risk 2.16-fold for homozygote carriers of the SNP. The second SNP, located in 11q23.1, increased CRC risk only in female SNP carriers by 3.08 for homozygotes and 1.49 for heterozygote SNP carriers.[30]

In a study of 684 mutation carriers from 298 Australian and Polish families, nine SNPs within six previous CRC susceptibility loci were genotyped to investigate their potential as modifiers of disease risk in LS.[31] Two SNPs, rs3802842 (11q23.1) and rs16892766 (8q23.3), were associated with CRC susceptibility in MLH1 mutation–positive LS patients. However, a subsequent study of 748 French MMR mutation carriers did not replicate the association between the IGF1 CA repeat and age of CRC onset or the association between SNPs in 8q23.3 and 11q23.1 and CRC risk.[32]

Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.


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Last Updated: February 25, 2014
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