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Colorectal Cancer: Genetics

  1. Ian M Frayling

Published Online: 27 JAN 2006

DOI: 10.1038/npg.els.0005555

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How to Cite

Frayling, I. M. 2006. Colorectal Cancer: Genetics. eLS. .

Author Information

  1. Department of Medical Genetics, Addenbrooke's Hospital, Cambridge, UK

Publication History

  1. Published Online: 27 JAN 2006

Introduction

  1. Top of page
  2. Introduction
  3. Development of Bowel Cancer
  4. Genetics of Bowel Cancer
  5. See also
  6. Further Reading
  7. Web Links

Epidemiology

Cancer of the large bowel is one of the commonest forms of cancer in the developed world affecting both sexes. In the developed world it therefore ranks third after lung and breast or prostate cancer: in 1996, 1 in 18 males and 1 in 20 females in the United Kingdom developed the disease. The majority of large bowel cancers are primary adenocarcinomas.

Anatomy

Although the large bowel appears to consist of a simple tube, it has a number of anatomically distinct regions. The main distinction is between the colon and rectum, together known as the colorectum and hence the term colorectal cancer. The colon and rectum, and tumors therein, exhibit biological differences. The embryological junction between the midgut and hind gut is located approximately two-thirds of the way along the transverse colon. The majority of large bowel cancers (75%) arise in the rectum and sigmoid colon, with about 10% arising in the cecum and the remainder elsewhere within the colon. Approximately 95% of colorectal adenocarcinomas arise from adenomas, benign tumors of the mucosal surface of the bowel that project into the bowel cavity (lumen). Bowel tumors arise as a result of a complex interaction between an individual's genetic make-up (genotype) and environmental/lifestyle factors, such as diet, physical exercise, obesity and, for females, reproductive history.

Development of Bowel Cancer

  1. Top of page
  2. Introduction
  3. Development of Bowel Cancer
  4. Genetics of Bowel Cancer
  5. See also
  6. Further Reading
  7. Web Links

Somatic mutations

As with all forms of neoplasia, bowel cancer develops by a stepwise accumulation of genetic mutations, each one conferring in Darwinian fashion a successively greater growth advantage on the cell in which it has arisen. As these mutations are acquired during life (i.e. they are not inherited in the germ line) they are known as somatic mutations. Mutations arise from a variety of causes; they may be termed ‘spontaneous’, but all mutations involve the making and breaking of covalent bonds. Mutations often result from damage to deoxyribonucleic acid (DNA) caused either by specific chemicals, called carcinogens, or, probably more commonly, by simple hydrolysis and oxidation. Individuals vary in their exposure to carcinogen precursors (prokarcinogens) and generation of oxidative species, as well as in their ability to metabolize prokarcinogens into carcinogens and carcinogens into harmless metabolites. In addition, DNA damage is repaired by a host of DNA repair systems, and individuals vary in their DNA repair capacity.

Much of the variation in carcinogen metabolism is due to genetic polymorphism in genes encoding metabolic enzymes, such as the cytochrome P-450 system (i.e. the CYP gene family), N-acetyl transferases (N-acetyltransferase 1 (arylamine N-acetyltransferase) (NAT1) and N-acetyltransferase 2 (arylamine N-acetyltransferase) (NAT2)) and glutathione S-transferases (glutathione S-transferase mu 1 (GSTM1), glutathione S-transferase pi 1 (GSTP1) and glutathione S-transferase theta 1 (GSTT1)). There is evidence that modest levels of risk may be conferred by some variants at some of these loci. See also Cancer Cytogenetics, Darwin and the Idea of Natural Selection, Darwin, Charles, and Environmental Mutagenesis

Germline mutations

Although the majority of mutations in cancers arise somatically, occasionally mutations in certain critical genes may be inherited in the germ line and predispose to bowel cancer, giving rise to individuals with a strong family history of bowel cancer. Such rare families have been instrumental in elucidating many of the major genetic changes that occur during the development of colorectal cancer.

Bowel cancer arises from benign tumours

Adenomas, the benign precursors of colorectal cancer, are common in the general population: approximately one in three individuals will develop an adenoma by the age of 70, but most adenomas (90%) will not progress to adenocarcinomas. A known risk factor is the development of more than one adenoma, implying a degree of predisposition to their development. At the extreme end of this scale are individuals who develop hundreds, sometimes thousands, of adenomas, usually at a young age (10–20 years). Without preventative treatment in the form of prophylactic surgical removal of the colon, such individuals are almost certain to develop bowel cancer. This condition, known as familial adenomatous polyposis (FAP), is covered in more detail elsewhere. See also Familial Adenomatous Polyposis

Genetics of Bowel Cancer

  1. Top of page
  2. Introduction
  3. Development of Bowel Cancer
  4. Genetics of Bowel Cancer
  5. See also
  6. Further Reading
  7. Web Links

Familial Adenomatous Polyposis, APC and bowel cancer

The gene responsible for FAP was originally narrowed down to the long arm of chromosome 5 (5q) after an individual with polyposis and learning difficulties was found to have a cytogenetic deletion of this region. Subsequently, in one of the first examples of the use of linked DNA markers, the gene was further localized, culminating in its identification and naming as adenomatous polyposis coli (APC). The mutations in APC found in FAP families are almost invariably inactivating and cause the APC protein to be prematurely terminated. Because the loss of APC function is associated with the development of bowel tumors, APC is classed as a tumor suppressor gene.

General Familial Risk

Apart from the rare instances of individuals with strong family histories, it is common for those in the general population who have been affected with colorectal cancer to have a family history of it in one or more close relatives, over and above that expected by chance. There have been over 30 studies of the degree to which colorectal cancer shows familiality, and all have shown that having a close relative with bowel cancer confers an increased risk of developing it. Combining these data has shown that the risk is increased 2.8-fold if an individual has a single first-degree relative who has developed bowel cancer. This risk is further increased if there have been more family members affected and/or if they have been affected at a young age. Having a first-degree relative who has developed an adenoma, rather than a cancer, also increases the risk of bowel cancer, but more modestly (1.8-fold).

The importance of APC in bowel cancer

Loss of one copy of chromosome 5q, in the process known as loss of heterozygosity (LOH) or allelic imbalance, is commonly observed in both colorectal adenomas and carcinomas. The frequency with which 5q is lost is the same in both adenomas and carcinomas (about 85%), and, moreover, this frequency is the same in small adenomas as in carcinomas. This implies that somatic mutation of APC is one of the earliest events in the development of adenomas, and is consistent with germline mutations of APC predisposing to the development of multiple adenomas. The effect of inactivating mutations in APC appears to be to reduce the activity of the APC protein in controlling cell adhesion and growth regulation. Normal function is achieved by a pathway involving regulation of the cell adhesion molecule E-cadherin by a cytoskeletal protein called β-catenin (homologous with the Wnt pathway in Drosophila). In tumors without APC mutation, activating mutations in β-catenin serve to inactivate the pathway. See also Familial Adenomatous Polyposis

Different forms of genetic instability in colorectal tumourigenesis

To start with the early mutations in adenomas are probably due to random events, but it is clear that at some stage in their progression some form of genomic instability occurs. This can take two forms: one is characterized by aneuploidy, that is, multiple chromosomal anomalies, such as triploidy, gain/loss of whole chromosome arms and translocations; the other is characterized by few chromosomal abnormalities (so the tumor's chromosome complement is what is termed ‘near diploid’) but widespread point mutations in the DNA, especially in repetitive sequences called microsatellites. This is known as microsatellite instability (MSI), whereas the other form of instability characterized by multiple chromosomal defects is associated with a lack of point mutations in microsatellites, known as microsatellite stability (MSS). See also Chromosomal Instability (CIN) in Cancer, and Microsatellites

Microsatellite instability and loss of DNA mismatch repair

The discovery of MSI in a proportion of colorectal cancers was made while studying families with strong histories of bowel cancer, like FAP, but without the multiple adenomas characteristic of FAP. Hence, these families were described as having hereditary nonpolyposis colorectal cancer (HNPCC) (also known as Lynch syndrome). While studying the tumors that had occurred in HNPCC families for LOH, as evidence that particular candidate genes were involved, it was found that instead of a loss of alleles at polymorphic microsatellites there was a paradoxical gain of alleles. This is what is termed MSI. This was recognized as a manifestation of a loss of a particular form of DNA repair called mismatch repair (MMR). This normally functions to make good abnormal base pairs in DNA, caused either by DNA damage or misincorporation of nucleotides during DNA synthesis, so-called replication errors. The system of MMR in Escherichia coli has three protein components, mutS, mutL and mutH. This has been highly conserved in evolution, although higher organisms have evolved families of homologous proteins. Thus, humans have, for example, MSH2 (mutS homolog 2), MSH6 and MLH1 (mutL homolog 1). A subfamily of proteins has evolved from the MLH family, and these were originally identified in yeast as genetic loci involved in the correct postmeiotic segregation of chromosomes: for example, PMS2 (postmeiotic segregation 2). It is intriguing that MMR is involved in the process of chromosomal recombination in eukaryotes and that loss of it is associated with tumors that do not undergo multiple chromosomal abnormalities. HNPCC is largely due to germline mutations in the MMR genes mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2) and mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1), but evidence is accruing of the importance of mutS homolog 6 (E. coli) (MSH6). See also Hereditary Nonpolyposis Colorectal Cancer, and Mismatch Repair Genes

Although MSI characterizes the tumors from HNPCC patients, it was quickly realized that a proportion (about 10–20%) of sporadic cancers of many kinds exhibited MSI. HNPCC is a rare condition affecting only one in every few thousand individuals; most tumors with MSI have thus arisen spontaneously. Some have made a distinction between low and high levels of MSI, but this is now thought to be artifactual, that is, if enough microsatellites are tested all tumors will eventually show some level of instability, but there is a distinct group of tumors with MSI. Approximately 20% of colon cancers have MSI, largely due to somatic methylation (5-methyl-cytidine methylation at CpG sites within a gene's promoter is an important mechanism of gene regulation in mammalian/human genes), usually associated with downregulation of the MLH1 gene promoter, whereas only a small proportion (about 1 in 20) are due to HNPCC; by contrast, only 1% of rectal cancers have MSI, mostly due to HNPCC. See also Methylation-mediated Transcriptional Silencing in Tumorigenesis

Other colorectal cancer-related genes

Other genetic loci that are involved in the pathogenesis of colorectal cancer depend to some extent on the pathway of genetic instability that the tumor has taken. Tumors with or without MSI show frequent involvement of v-Ki-ras2 Kirsten rat sarcoma 2 viral oncogene homolog (KRAS2), an oncogene activated by mutations at one of three specific codons. Tumors without MSI tend to show involvement of MAD, mothers against decapentaplegic homolog 4 (Drosophila) (MADH4) and tumor protein p53 (Li–Fraumeni syndrome) (TP53), whereas those with MSI tend to involve transforming growth factor, beta 1 (Camurati–Engelmann disease) (TGFB1) and BCL2-associated X protein (BAX) instead. Just as colorectal tumors show mutations of APC or β-catenin, which derange the same pathway, so they show MADH4 or TGFB1 (same pathway), or TP53 or BAX (same pathway). This implies that derangement of these pathways needs to occur, but the precise mechanism depends on the underlying type of genomic instability. It was originally thought that the locus on 18q that was the target of LOH was a gene called deleted in colorectal carcinoma (DCC); this may be the case, but a more likely candidate is MADH4. Germline mutations in MADH4 are responsible for some cases of familial juvenile polyposis, a rare condition predisposing to bowel cancer via the development of polyps with a distinctive histology.

Another locus associated with unusual polyps of distinct histology is serine/threonine kinase 11 (Peutz–Jeghers syndrome) (STK11), responsible for Peutz–Jeghers syndrome, a rare inherited cancer syndrome. In addition, it has been shown that mutations in mutY homolog (E. coli) (MUTYH), which encodes a DNA repair enzyme active against oxidative damage, can predispose to multiple adenomas, mimicking FAP due to APC mutations, except that the mode of inheritance is recessive (as for all other hereditary DNA repair deficiencies), not dominant. The loss of DNA repair in HNPCC is not constitutional, rather HNPCC only predisposes to loss of MMR within tumors, so HNPCC is not typical of hereditary DNA repair deficiencies. See also DNA Repair, DNA Repair: Disorders, Hamartomatous Polyposis Syndromes: Peutz–Jeghers Syndrome and Familial Juvenile Polyposis, and Li-Fraumeni Syndrome

Further Reading

  1. Top of page
  2. Introduction
  3. Development of Bowel Cancer
  4. Genetics of Bowel Cancer
  5. See also
  6. Further Reading
  7. Web Links

Web Links

  1. Top of page
  2. Introduction
  3. Development of Bowel Cancer
  4. Genetics of Bowel Cancer
  5. See also
  6. Further Reading
  7. Web Links