APC I1307K
Genetic Variation in 8q24 and SMAD7

It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[1] Based on epidemiological studies, the risk of colon cancer in a first-degree relative of an affected individual can increase an individual’s lifetime risk of colon cancer 2-fold to 4.3-fold.[2] The relative and absolute risk of colorectal cancer for different family history categories is estimated in Table 1. In addition, the lifetime risk of colon cancer also increases in first-degree relatives of individuals with colon adenomas.[3] The magnitude of risk depends on the age at diagnosis of the index case, the degree of relatedness of the index case to the at-risk case, and the number of affected relatives. It is currently believed that many of the moderate- and low-risk cases are influenced by low-penetrance genes or gene combinations. Given the public health impact of identifying the etiology of this increased risk, an intense search for the responsible genes is under way.

Several candidate genes have been identified and their potential use for clinical genetic testing is being determined. Candidate alleles that have been shown to associate with a modest increased frequencies of colon cancer include heterozygous BLM^Ash (the allele that is a founder mutation in Ashkenazi Jewish individuals with Bloom syndrome), the GH1 1663 T→A polymorphism (a polymorphism of the growth hormone gene associated with low levels of growth hormone and IGF-1), and the APC I1307K polymorphism.[4-6]

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.[6,7] 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 may not be 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.

Genome-wide association studies of colorectal cancer have identified several new susceptibility loci that have been reproduced in multiple populations. Three separate studies showed that genetic variation at 8q24.21 is associated with increased risk of colon cancer, with relative risks ranging from 1.17 to 1.27.[8-10] Although the relative risk 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.[11]

Other candidate alleles that have been identified on multiple (more than three) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[12] None of these alleles, including the APC I1307K polymorphism, have 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.[13]

References

1. Burt RW, Bishop DT, Lynch HT, et al.: Risk and surveillance of individuals with heritable factors for colorectal cancer. WHO Collaborating Centre for the Prevention of Colorectal Cancer. Bull World Health Organ 68 (5): 655-65, 1990.  [PUBMED Abstract]
   
   
2. Butterworth AS, Higgins JP, Pharoah P: Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur J Cancer 42 (2): 216-27, 2006.  [PUBMED Abstract]
   
   
3. Johns LE, Houlston RS: A systematic review and meta-analysis of familial colorectal cancer risk. Am J Gastroenterol 96 (10): 2992-3003, 2001.  [PUBMED Abstract]
   
   
4. Gruber SB, Ellis NA, Scott KK, et al.: BLM heterozygosity and the risk of colorectal cancer. Science 297 (5589): 2013, 2002.  [PUBMED Abstract]
   
   
5. Le Marchand L, Donlon T, Seifried A, et al.: Association of a common polymorphism in the human GH1 gene with colorectal neoplasia. J Natl Cancer Inst 94 (6): 454-60, 2002.  [PUBMED Abstract]
   
   
6. Laken SJ, Petersen GM, Gruber SB, et al.: Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APC. Nat Genet 17 (1): 79-83, 1997.  [PUBMED Abstract]
   
   
7. Lothe RA, Hektoen M, Johnsen H, et al.: The APC gene I1307K variant is rare in Norwegian patients with familial and sporadic colorectal or breast cancer. Cancer Res 58 (14): 2923-4, 1998.  [PUBMED Abstract]
   
   
8. Zanke BW, Greenwood CM, Rangrej J, et al.: Genome-wide association scan identifies a colorectal cancer susceptibility locus on chromosome 8q24. Nat Genet 39 (8): 989-94, 2007.  [PUBMED Abstract]
   
   
9. Tomlinson I, Webb E, Carvajal-Carmona L, et al.: A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat Genet 39 (8): 984-8, 2007.  [PUBMED Abstract]
   
   
10. Gruber SB, Moreno V, Rozek LS, et al.: Genetic Variation in 8q24 Associated with Risk of Colorectal Cancer. Cancer Biol Ther 6 (7): , 2007.  [PUBMED Abstract]
    
    
11. Broderick P, Carvajal-Carmona L, Pittman AM, et al.: A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet 39 (11): 1315-7, 2007.  [PUBMED Abstract]
    
    
12. Hirschhorn JN, Lohmueller K, Byrne E, et al.: A comprehensive review of genetic association studies. Genet Med 4 (2): 45-61, 2002 Mar-Apr.  [PUBMED Abstract]
    
    
13. Zheng SL, Sun J, Wiklund F, et al.: Cumulative association of five genetic variants with prostate cancer. N Engl J Med 358 (9): 910-9, 2008.  [PUBMED Abstract]
    
    

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