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Genetics of Colorectal Cancer (PDQ®)

Colon Cancer Genes

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important mutations (e.g., nonsense, missense, frameshift) of the gene as causal mechanisms. Major genes are typically considered those that are involved in single-gene disorders, and the diseases caused by major genes are often relatively rare. Most pathogenic mutations in major genes lead to a very high risk of disease, and environmental contributions are often difficult to recognize.[1] Historically, most major colon cancer susceptibility genes have been identified by linkage analysis using high-risk families; thus, these criteria were fulfilled by definition, as a consequence of the study design.

The functions of the major colon cancer genes have been reasonably well characterized over the past decade. Three proposed classes of colon cancer genes are tumor suppressor genes, oncogenes, and DNA repair genes.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for both familial adenomatous polyposis (FAP) and juvenile polyposis syndrome (JPS), among others. Germline mutations of oncogenes are not an important cause of inherited susceptibility to colorectal cancer (CRC), even though somatic mutations in oncogenes are ubiquitous in virtually all forms of gastrointestinal cancers. Stability genes, especially the mismatch repair (MMR) genes responsible for Lynch syndrome (LS) (also called hereditary nonpolyposis colorectal cancer [HNPCC]), account for a substantial fraction of hereditary CRC, as noted below. (Refer to the Lynch syndrome [LS] section in the Major Genetic Syndromes section of this summary for more information). MYH is another important example of a stability gene that confers risk of CRC based on defective base excision repair. Table 2 summarizes the genes that confer a substantial risk of CRC, with their corresponding diseases.

Table 2. Genes Associated with a High Susceptibility of Colorectal Cancer
Gene Syndrome Hereditary Pattern Predominant Cancer
FAP = familial adenomatous polyposis; JPS = juvenile polyposis syndrome; LS = Lynch syndrome; OMIM = Online Mendelian Inheritance in Man database; PJS = Peutz-Jeghers syndrome.
Tumor suppressor genes      
APC (OMIM) FAP Dominant Colon, intestine, etc.
TP53 (p53) (OMIM) Li-Fraumeni Dominant Multiple (including colon)
STK11 (LKB1) (OMIM) PJS Dominant Multiple (including intestine)
PTEN (OMIM) Cowden Dominant Multiple (including intestine)
BMPR1A (OMIM) JPS Dominant Gastrointestinal
SMAD4 (MADH/DPC4) (OMIM) JPS Dominant Gastrointestinal
Repair/stability genes      
MLH1 (OMIM), MSH2 (OMIM), MSH6 (OMIM), PMS2 (OMIM) LS Dominant Multiple (including colon, uterus, and others)
EPCAM (TACSTD1) (OMIM) LS Dominant Multiple (including colon, uterus, and others)
MYH (MUTYH) (OMIM) MYH-associated polyposis Recessive Colon
POLD1 (OMIM), POLE (OMIM) Oligopolyposis Dominant Colon, endometrial

De Novo Mutation Rate

Until the 1990s, the diagnosis of genetically inherited polyposis syndromes was based on clinical manifestations and family history. Now that some of the genes involved in these syndromes have been identified, a few studies have attempted to estimate the spontaneous mutation rate (de novo mutation rate) in these populations. Interestingly, FAP, JPS, Peutz-Jeghers syndrome, Cowden syndrome, and Bannayan-Riley-Ruvalcaba syndrome are all thought to have high rates of spontaneous mutations, in the 25% to 30% range,[3-5] while estimates of de novo mutations in the MMR genes associated with LS are thought to be low, in the 0.9% to 5% range.[6-8] These estimates of spontaneous mutation rates in LS seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9-11] making the de novo mutation rate for LS seem quite low in contrast to the relatively high rates in the other polyposis syndromes.

Genetic Polymorphisms and CRC Risk

It is widely acknowledged that the familial clustering of colon cancer also occurs outside of the setting of well-characterized colon cancer family syndromes.[12] 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.[13] The relative risk (RR) and absolute risk of 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.[14] 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 LS or 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 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 (e.g., 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.[15-17]

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 the susceptibility to CRC,[18] and causative germline mutations account for less than 6% of all CRC cases.[19] 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.[20,21] 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.[22] 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).[23] 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. Carrying all six possible risk alleles yielded an estimated 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.[24] 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 result from a correlation with common coding variants and many of the loci map to regions lacking genes of protein-coding transcripts, much of the common variation in cancer risk is likely 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.[25] 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 cancers) before analysis.[26] 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 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.[27] 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
ORhet = odds ratio among heterozygotes; ORhom = odds ratio among homozygotes.
aIdentified in a breast/colon cohort.
3q29 LOD = 2.61 [27] .0003   D3S240
4q31.3 LOD = 2.13 [27] .0009   D4S2999
7q31.31 LOD = 3.08 [27] .00008   D7S643
8q23.3 Combined OR = 1.29 [24] 1.1 × 10-10 rs11986063  
8q23.3 ORallelic = 1.25, ORhet = 1.27, ORhom = 1.43 [22] 3.3 × 10-18 rs16892766  
Combined OR = 1.32 [24] 1.1 × 10-10
8q24 ORallelic = 1.24, ORhet = 1.35, ORhom = 1.57 [22] 7.0 × 10-11 rs6983267  
Combined OR = 0.83 [24] 2.1 × 10-14
8q24 OR = 1.19 [23] 8.6 × 10-26 rs7014346  
Combined OR = 1.21 [24] 3.0 × 10-13
8q24 Combined OR = 1.17 [24] 1.2 × 10-10 rs7837328  
8q24 Combined OR = 1.14 [24] 1.5 × 10-7 rs10808555  
10p14 ORallelic = 0.89, ORhet = 0.87, ORhom = 0.80 [22] 2.5 × 10-13 rs10795668  
Combined OR = 0.91 [24] 3.1 × 10-4
11q23 OR = 1.11 [23] 5.8 × 10-10 rs3802842  
Combined OR = 1.21 [24] 5.2 × 10-13
14q22.2 Combined OR = 1.11 [24] 8.1 × 10-10 rs4444235  
15q13 ORallelic = 1.23, ORhet = 1.17, ORhom = 1.70 [22] 4.7 × 10-7 rs4779584  
Combined OR = 1.19 [24] 1.7 × 10-8
16q22.1 Combined OR = 0.91 [24] 1.2 × 10-8 rs9929218  
17p13.3a Not available [26] .0364   D17S1308
18q21 ORallelic = 0.85, ORhet = 0.84, ORhom = 0.73 [22] 1.7 × 10-6 rs4939827  
OR = 1.20 [23] 7.8 × 10-28
Combined OR = 0.85 [24] 2.2 × 10-11
19q13.1 Combined OR = 0.89 [24] 2.2 × 10-7 rs7259371  
19q13.1 Combined OR = 0.87 [24] 4.6 × 10-9 rs10411210  
20p12.3 Combined OR = 1.12 [24] 2.0 × 10-10 rs355527  
20p12.3 Combined OR = 1.12 [24] 2.1 10-10 rs961253  

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 are noted. 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.[28-30] 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.[31]

Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[32] 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.[33,34]

Variants of Uncertain Significance in Major Cancer Susceptibility Genes
APC I1307K

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.[17,35] 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.[17] 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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  • Updated: February 20, 2015