Genetics of Colorectal Cancer (PDQ®) 2/6 –Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)–Health Professional Version - National Cancer Institute

Genetics of Colorectal Cancer (PDQ®)–Health Professional Version

Colorectal Cancer Susceptibility Genes

In This Section

• Major Genes
• De Novo Pathogenic Variant Rate
• Genetic Polymorphisms and CRC Risk
  • Polymorphism-modifying risk in average-risk populations

Major Genes

Major genes are defined as those that are necessary and sufficient for disease causation, with important pathogenic variants (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 variants 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 colorectal (CRC) cancer genes have been reasonably well characterized over the past decade.[2] Tumor suppressor genes constitute the most important class of genes responsible for hereditary cancer syndromes and represent the class of genes responsible for familial adenomatous polyposis (FAP), Lynch syndrome, and juvenile polyposis syndrome (JPS), among others. 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; PJS = Peutz-Jeghers syndrome; PPAP = polymerase proofreading–associated polyposis.
APC	FAP, AFAP	Dominant	Colorectal, small bowel, gastric, etc.
TP53 (p53)	Li-Fraumeni	Dominant	Multiple (including colorectal)
STK11 (LKB1)	PJS	Dominant	Multiple (including colorectal, small bowel, pancreas)
PTEN	Cowden	Dominant	Multiple (including colorectal)
BMPR1A, SMAD4 (MADH/DPC4)	JPS	Dominant	Gastric and colorectal
MLH1, MSH2, MSH6, PMS2, EPCAM	Lynch syndrome	Dominant	Multiple (including colorectal, endometrial, and others)
MUTYH (MYH)	MUTYH-associated polyposis	Recessive	Colorectal
POLD1, POLE	PPAP	Dominant	Colorectal, endometrial

De Novo Pathogenic Variant 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 pathogenic variant rate (de novo pathogenic variant 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 pathogenic variants, in the 25% to 30% range,[3-5] while estimates of de novo pathogenic variants in the MMR genes associated with Lynch syndrome are thought to be low, in the 0.9% to 5% range.[6-8] These estimates of spontaneous pathogenic variant rates in Lynch syndrome seem to overlap with the estimates of nonpaternity rates in various populations (0.6% to 3.3%),[9-11] making the de novo pathogenic variant rate for Lynch syndrome 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 alterations in single low-penetrance genes or combinations of low-penetrance genes. 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 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 pathogenic variants 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 Lynch syndrome. Additionally, polymorphisms in genes distinct from the MMR genes can modify phenotype (e.g., average age of CRC) in individuals with Lynch syndrome.

Low-penetrance variants have been identified in a number of strategies. Earlier studies focused on candidates genes chosen because of biologic relevance to cancer pathogenesis. More recently, genome-wide association studies (GWAS) have been used much more extensively to identify potential CRC susceptibility genes. (Refer to the GWAS section of this summary for more information.) Another approach is to use meta-analyses of existing GWAS datasets to discover additional novel CRC susceptibility genes.

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 pathogenic variant 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.)

GWAS

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 Lynch syndrome cases fail to have a pathogenic variant 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 pathogenic variants account for less than 6% of all CRC cases.[19] This suggests that there may be other major genes with pathogenic variants that may predispose to CRC with or without polyposis. A few such genes have been detected (e.g., MUTYH, 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 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 pathogenic variants, 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 in thousands of CRC cases and controls has led to the discovery of multiple common low-risk CRC SNPs, which can be found in the National Human Genome Research Institute GWAS catalogExit Disclaimer. A thorough discussion of GWAS can be found in the Cancer Genetics Overview PDQ summary. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes are governed by many alleles, each conferring modest risk. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an odds ratio (OR) for disease risk of less than 1.5.

Meta-analysis of GWAS has allowed for the identification of novel CRC-associated SNPs by combining data from previous GWAS.[22,22-25] These SNPs are provided in the GWAS catalogExit Disclaimer referenced above. The same considerations for GWAS mentioned above apply to the meta-analysis approach.

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.[26-28] 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.[29]

Other candidate alleles that have been identified on multiple (>3) genetic association studies include the GSTM1 null allele and the NAT2 G/G allele.[30] 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.[31,32]

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.[17,33] The I1307K polymorphism results from a transition from T to 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 mechanisms 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.

Polygenic risk scores for colorectal cancer

There is increasing interest in using SNPs to expand germline risk assessment from monogenic high-/moderate-penetrance forms of CRC predisposition to polygenic forms of CRC risk assessment that may have broader applicability to the general population. To that end, multiple studies have examined the utility of polygenic risk scores (PRSs) to personalize CRC risk assessment in individuals otherwise considered to be at average risk for CRC.

One study examined 36 different SNPs previously linked to CRC susceptibility by GWAS in 341 men with CRC and 329 controls from a population-based registry of Japanese individuals. Investigators ultimately identified six of these SNPs to be associated with CRC risk in this population and constructed a PRS, which had reasonable discriminatory capacity (area under the curve [AUC], 0.63) for assessing a 10-year absolute risk of CRC. The investigators found that the performance of the PRS was marginally superior to a previously validated nongenetic risk prediction score (AUC, 0.60) incorporating age, body mass index, and tobacco and alcohol use, and found that a combined model including both SNP data and these nongenetic factors had superior discriminatory capacity for assessing a 10-year absolute CRC risk (AUC, 0.66).[34] Likewise, another study examined the use of a PRS consisting of 48 SNPs previously linked to CRC risk by GWAS in 1,043 German individuals aged 50 to 79 years undergoing screening colonoscopy.[35] Investigators demonstrated that the PRS effectively discriminated between risk for advanced neoplasms (carcinoma or advanced adenomas) versus nonadvanced adenomas and normal colonoscopic findings. Participants with the highest tertile of PRS were estimated to have the same risk of advanced colorectal neoplasm as participants 17.5 years older from the lowest tertile of PRS, suggesting that such PRS data may help estimate individuals’ risk sufficiently well to allow for personalized recommendations regarding age at initiation of colonoscopic screening in individuals previously considered at average risk for CRC. Interestingly, another case-control study of 2,363 patients with CRC and 2,198 controls demonstrated that a 53 SNP PRS and family history of CRC were both associated with increased CRC risk, but that these associations appeared to be independent of one another.[36] Investigators concluded that PRS may thus substantially augment family history-based CRC risk stratification, and that GWAS-identified SNPs associated with CRC risk may not be the factor underlying most familial CRC clustering.

Despite such promising data, however, it is important to emphasize that such PRSs are not currently used in routine clinical settings and are not currently considered to be clinically actionable. Formal implementation studies examining the use of such PRSs to guide CRC risk assessment and screening in routine clinical care are warranted, on the basis of these encouraging data.

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