Genetic Polymorphisms and Colorectal Cancer Risk
Polymorphism-Modifying Risk in Average-Risk Populations
Low-penetrance candidate genes
Genetic Variation in 8q24 and SMAD7
Variants of Uncertain Significance in Major Cancer Susceptibility Genes
Clinical implications of low-penetrance alleles
Polymorphisms in Unrelated Genes Affecting Expression in LS
It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes. 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. The relative risk (RR) and absolute risk of colorectal cancer (CRC) 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. 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.
Each locus would be expected to have a relatively small effect on CRC risk and would not produce the dramatic familial aggregation seen in Lynch syndrome (LS) or familial adenomatous polyposis (FAP). However, in combination with other common genetic loci and/or environmental factors, variants of this kind might significantly alter CRC risk. These types of genetic variations are often referred to as polymorphisms. Most loci that are polymorphic have no influence on disease risk or human traits (benign polymorphisms), while those that are associated with a difference in risk of disease or a human trait (however subtle) are sometimes termed disease-associated polymorphisms or functionally relevant polymorphisms. When such variation involves changes in single nucleotides of DNA they are referred to as single nucleotide polymorphisms (SNPs).
Polymorphisms underlying polygenic susceptibility to CRC are considered low penetrance, a term often applied to sequence variants associated with a minimal to moderate risk. This is in contrast to high-penetrance variants or alleles that are typically associated with more severe phenotypes, for example those APC or mismatch repair (MMR) gene mutations leading to an autosomal dominant inheritance pattern in a family. The definition of a moderate risk of cancer is arbitrary, but it is usually considered to be in the range of an RR of 1.5 to 2.0. Because these types of sequence variants are relatively common in the population, their contribution to total cancer risk is estimated to be much higher than the attributable risk in the population from the relatively rare syndromes such as FAP or LS. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (for example average age of CRC) in individuals with LS.
In general, low-penetrance variants have been identified in one of two manners. Earlier studies focused on candidates genes chosen because of biologic relevance to colon cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the Genome-wide searches section of this summary for more information.)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.[4-6]
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.)Genome-wide searches
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.
A GWAS using 555,510 SNPs in 14,500 cases of CRC and 13,294 controls from seven different centers revealed a previously unreported association on 11q23 (odds ratio [OR], 1.1; P = 5.8 × 10-10) and replicated susceptibility loci at 8q24 (OR, 1.19; P = 8.6 × 10-26) and 18q21 (OR, 1.2; P = 7.8 × 10-28). Furthermore, the authors were unable to identify causative coding sequence variants in any of the candidate genes at 8q24 (POU5F1P1, HsG57825, and DQ515897) or 18q21 (SMAD7). The variants identified are common in the general population, with risk-allele frequencies in populations of European ancestry of 0.29, 0.37, and 0.52, respectively. It was estimated that carrying all six possible risk alleles yielded an OR of 2.6 (95% confidence interval [CI], 1.75–3.89) for CRC.
A meta-analysis of GWAS data obtained from the two studies above (the combined dataset analyzed contained 38,710 polymorphic SNPs in 2,024 cases and 2,092 controls) revealed four additional susceptibility loci. In addition to six loci identified in previous GWAS (8q23, 8q24, 10p14, 11q23, 15q13, and18q21), the following four new loci were identified:
- Two SNPs linked to a 38 kilobase (kb) region on 20p12.3 [two SNPs: (i) combined OR, 1.12; 95% CI, 1.08–1.16; P = 2.0 × 10-10 and (ii) combined OR, 1.12; 95% CI, 1.08–1.17; P = 2.1 × 10-10] lacking genes or predicted protein-encoding transcripts;
- 14q22.2 (combined OR, 1.11; 95% CI, 1.08–1.15; P = 8.1 × 10-10) in a region 9.4kb from the transcription start site of the BMP4 gene;
- 19q13.1 [two SNPs: (i) combined OR, 0.87; 95% CI, 0.83–0.91; P = 4.6 × 10-9 and (ii) combined OR, 0.89; 95% CI, 0.85–0.93; P = 2.2 , 10-7], which lies within the Rho GTPase binding protein 2 (RHPN2) gene; and
- 16q22.1 (combined OR, 0.91; 95% CI, 0.89–0.94; P = 1.2 × 10-8), which lies within intron 1 of the E-cadherin (CDH1) gene.
No interactions between the loci were associated with an increased risk of CRC and the loci identified were estimated to collectively account for approximately 6% of the excess familial risk of CRC. The data analyses led the authors to conclude the following:
- The loci readily detectable through current GWAS are associated with modest effects (genotypic risks of approximately 1.2).
- The number of common variants explaining more than 1% of inherited risk is very low.
- Only a small proportion of heritability of any cancer can be explained by the currently identified loci.
- Of the common risk loci identified thus far, no significant epistatic effects were observed.
Because few of the observed associations seem to be due to correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, it seems likely that much of the common variation in cancer risk is mediated through sequence changes influencing gene expression.
A genome-wide linkage analysis was performed in 30 Swedish non-FAP/non-LS families with a strong family history of CRC. Several loci on chromosomes 2q, 3q, 6q, and 7q with suggestive linkage were detected by parametric and nonparametric analysis.
A GWAS of affected, unaffected, and discordant sibling pairs in 194 kindreds utilized clinical information (histopathology, size and number of polyps, and other primary cancers) in conjunction with age at onset and family history to define five phenotypic subgroups (severe histopathology, oligopolyposis, young, colon/breast, and multiple cancer) prior to analysis. 1p31.1 strongly linked to the multiple-cancer subgroup (P < .00007). 15q14-q22 linked to the full-sample (P < .018), oligopolyposis (P < .003), and young (P < .0009) phenotypes. This region includes the HMPS/CRAC1 locus associated with hereditary mixed polyposis syndrome (HMPS) in families of Ashkenazi descent. BRCA2 linked with the colon/breast phenotypic subgroup. Linkage to 17p13.3 in the breast/colon subgroup identified HIC1 (hypermethylated in colon cancer 1) as a candidate gene.
Nonparametric analysis revealed three loci at 3q29 (logarithm of the odds [LOD] score = 2.61; P = .0003), 4q31.3 (LOD = 2.13; P = .0009), and 7q31.31 (LOD = 3.08; P = .00008) in a GWAS performed in 70 kindreds with at least two siblings affected with colorectal adenocarcinoma or colorectal polyps with high-grade dysplasia. Linkage to 8q24, 9q22, and 11q23 was not obtained in these kindreds. Minor linkage to 3q21-q24 was present in this study population.Table 3. Colorectal Cancer Susceptibility Loci Identified Through Genome-Wide Association Studies
|Chromosome||Logarithm of the Odds (LOD) Score/Odds Ratio (OR)||P Value||Single Nucleotide Polymorphism (SNP)||Marker|
|3q29||LOD = 2.61 ||.0003||D3S240|
|4q31.3||LOD = 2.13 ||.0009||D4S2999|
|7q31.31||LOD = 3.08 ||.00008||D7S643|
|8q23.3||Combined OR = 1.29 ||1.1 × 10-10||rs11986063|
|8q23.3||ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43 ||3.3 × 10-18||rs16892766|
|Combined OR = 1.32 ||1.1 × 10-10|
|8q24||ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57 ||7.0 × 10-11||rs6983267|
|Combined OR = 0.83 ||2.1 × 10-14|
|8q24||OR = 1.19 ||8.6 × 10-26||rs7014346|
|Combined OR = 1.21 ||3.0 × 10-13|
|8q24||Combined OR = 1.17 ||1.2 × 10-10||rs7837328|
|8q24||Combined OR = 1.14 ||1.5 × 10-7||rs10808555|
|10p14||ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80 ||2.5 × 10-13||rs10795668|
|Combined OR = 0.91 ||3.1 × 10-4|
|11q23||OR = 1.11 ||5.8 × 10-10||rs3802842|
|Combined OR = 1.21 ||5.2 × 10-13|
|14q22.2||Combined OR = 1.11 ||8.1 × 10-10||rs4444235|
|15q13||ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70 ||4.7 × 10-7||rs4779584|
|Combined OR = 1.19 ||1.7 × 10-8|
|16q22.1||Combined OR = 0.91 ||1.2 × 10-8||rs9929218|
|17p13.3a||Not available ||.0364||D17S1308|
|18q21||ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73 ||1.7 × 10-6||rs4939827|
|OR = 1.20 ||7.8 × 10-28|
|Combined OR = 0.85 ||2.2 × 10-11|
|19q13.1||Combined OR = 0.89 ||2.2 × 10-7||rs7259371|
|19q13.1||Combined OR = 0.87 ||4.6 × 10-9||rs10411210|
|20p12.3||Combined OR = 1.12 ||2.0 × 10-10||rs355527|
|20p12.3||Combined OR = 1.12 ||2.1 10-10||rs961253|
|ORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes.|
|aIdentified in a breast/colon cohort.|
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 and SMAD7
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.[17-19] 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.
Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele. 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. 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.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.
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. 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.
Given the inconsistent results of these studies, genetic testing for these polymorphisms has no clinical utility at present.References
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