Polymorphism-Modifying Risk in Average-Risk Populations
Low-penetrance candidate genes
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 modest increased frequencies of colon cancer include heterozygous BLMAsh (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.[4,5,6]
Of these, the variant that has been most extensively studied is APC I1307K. Yet, neither it nor any of the other variants mentioned above are routinely used in clinical practice. (Refer to the APC I1307K section of this summary for more information.)
Although the major genes for polyposis and nonpolyposis inherited CRC syndromes have been identified, between 20% and 50% of cases from any given series of suspected FAP or LS cases fail to have a mutation detected by currently available technologies. It is estimated that heredity is responsible for approximately one-third of our susceptibility to CRC, and causative germline mutations account for less than 6% of all CRC cases. This has led to suspicions that there may be other major genes that, when mutated, predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MYH, EPCAM) but the probability for discovery of other such genes is fairly low. More recent measures for new gene discovery have taken a genome-wide approach. Several GWAS have been conducted with relatively large, unselected series of CRC patients that have been evaluated for patterns of polymorphisms in candidate and anonymous genes spread throughout the genome. These SNPs are chosen to capture a large portion of common variation within the genome, based on the International HapMap Project.[9,10] The goal is to identify alleles that, while not pathologically mutated, may confer an increase (or potential decrease) in CRC risk. Identification of yet unknown aberrant CRC alleles would permit further stratification of at-risk individuals on a genetic basis. Such risk stratification would potentially enhance CRC screening. The use of genome-wide scans has led to the discovery of multiple common low-risk CRC susceptibility alleles. Refer to Table 3 for more information.
A large GWAS was performed using tagSNPs in a total of 10,731 CRC cases and 10,961 controls from eight centers to identify and enrich for CRC susceptibility alleles. In addition to the previously reported 8q24, 15q13, and 18q21 CRC risk loci, two previously unreported associations at 10p14 (P = 2.5 × 10-13) and 8q23.3 (P = 3.3 × 10-8) were identified. The 8q23.3 locus tags a plausible causative gene, EIF3H (OMIM). The authors of this study estimated that the loci identified account for approximately 3% to 4% of the excess familial CRC risk, but that a high proportion of the population would be carriers of at-risk genotypes. They estimated that 3% of individuals may carry seven or more deleterious alleles. The authors concluded that their data are compatible with a polygenic model in which individual alleles, each exerting a small effect, combine either additively or multiplicatively to produce much larger risks in carriers of multiple risk alleles.