Cancer genes
This page presents information on oncogenes, tumour suppressor genes, and caretaker genes. Also, multi-step process and cancer, the cancer genome project, epigenetics and cancer, and other factors affecting cancer development
Of the estimated 20–25,000 genes in the human genome,1 currently more than 300 are known to play a role in the development of cancer.2
There are two main classes of these ‘cancer genes’: oncogenes and tumour suppressor genes. A third class, a sub-type of tumour suppressor genes called the caretaker genes, is also now recognised.3 Mutations in cancer genes can be inherited (see Inherited cancer risk) but, in the majority of cases, they occur during a person’s lifetime.
A number of different types of genetic alteration can occur; some of the more common types are described in Figure 2.1.
Oncogenes and cancer
Oncogenes cause normal cells to grow out of control and become cancer cells. They are mutated forms of normal genes called proto-oncogenes.
Proto-oncogenes normally control how often a cell divides and the degree to which it differentiates. When a proto-oncogene mutates into an oncogene, usually through amplification, translocation or point mutation, it becomes permanently ‘turned on’ or activated when it is not supposed to be. When this occurs, the cell divides too quickly, which can lead to cancer. Only one of the two alleles of a proto-oncogene needs to be overactive in order to have an oncogenic effect.
Examples of human oncogenes are shown in Table 2.1.
An example of an oncogene is BCR-ABL. This is formed by a translocation between sections of human chromosomes 9 and 22, resulting in what is known as the Philadelphia chromosome.4 The resulting Bcr-Abl protein interferes with signalling pathways within cells and causes the over-production of white blood cells, leading to chronic myeloid leukaemia (CML).5 As the Bcr-Abl fusion protein is unique to leukaemic cells it presents a potential target for treatment (see New targets for diagnosis and treatment).
Tumour suppressor genes
Tumour suppressor genes encode proteins that normally slow down cell division, repair DNA mistakes, and trigger apoptosis. Inactivation of tumour suppressor genes can lead to cells growing out of control, which can lead to cancer.
Inactivation can occur through point mutation, deletion or epigenetic mechanisms (For more information, see our section on Epigenetics). While most oncogenes develop from mutations acquired during the life of the individual, mutations of tumour suppressor genes can be inherited as well as acquired (see Inherited cancer risk).
Examples of human tumour suppressor genes are shown in Table 2.1 above. One of these, the TP53 gene, is the most frequently inactivated gene in human cancers. It normally encodes a pivotal transcription factor that puts a brake on abnormal cell growth and triggers apoptosis in cells that have sustained DNA damage.
Originally, it was believed that both alleles of a tumour suppressor gene must be mutated in order to render it inactive.6 This ‘two-hit’ model of tumour suppressor inactivation has provided a useful conceptual framework for research on the genetics and biology of tumour suppressor genes.
But more recently some evidence has emerged that mutations in tumour suppressor genes are not always completely recessive; some tumour suppressor genes need only one allele to be mutated to produce an oncogenic effect.
These single allele mutations can act by producing a dominant-negative protein (a protein whose abnormal function ‘overpowers’ that of the normal protein), or by altering the total amount of protein produced. reviewed in 7,8
Caretaker genes
These are a class of tumour suppressor genes but, as they do not regulate cell division, their inactivation is not directly responsible for cancer development. Many caretaker genes, also known as ‘stability genes’ 3, are involved in recognising and repairing DNA damage. Their inactivation causes genetic instability and leads to increases in the mutation rate of all genes, including oncogenes and tumour suppressor genes.3
Examples of caretaker genes are shown in Table 2.1 above.
Multi-step process and cancer
The development of cancer requires the accumulation of mutations in a number of key genes. Different tissues and types of cells will require different combinations of genes to be mutated in order to become cancerous.
A study of breast and colorectal cancer cell lines has shown that these cancer cells may harbour an average of around 90 mutant genes.9 But only a few of these mutations will actually be responsible for the development of the cancer.For example, some scientists have estimated that a minimum of five genetic alterations is needed for the development of colon cancer.10 The other mutations are known as ‘bystander’ 11 or ‘passenger’ 9 mutations and confer neither a growth advantage nor disadvantage. They are especially common in tumours in which caretaker genes are mutated.11
In sporadic cases of cancer, the initial genetic alteration occurs in a single cell. If this is not repaired, it is passed to daughter cells during cell division. If one of these daughter cells acquires a further genetic alteration(s), it passes this and the original alteration on to its daughter cells.
If this process is repeated a number of times, populations of increasingly abnormal cells are formed (Figure 2.2). Eventually, this leads to the development of a cancer capable of invasion and spread.12
Although historically the initial genetic alteration was thought to occur in a differentiated cell, increasingly, scientists believe that cancers actually arise from stem cells. reviewed in 13,14
Figure 2.2 the multi-step development of cancer.
The Cancer Genome Project
A large number of genes involved in cancer development have now been identified and, in the wake of the sequencing of the human genome, intensive efforts are underway to identify others. One such initiative, the Cancer Genome Project, began in 2000 and is comparing the genetic make-up of cancer cells and normal cells to identify genes involved in the development and progression of the disease.2
This research is exploiting the latest high-throughput mutation detection technology and will accelerate the rate of discovery of new molecular targets for diagnosis and treatment. An early success of the project was the identification of B-RAF, an oncogene that is frequently mutated in melanoma and other cancers.15
Epigenetics and cancer
Epigenetics is the study of mechanisms that alter gene expression and activity, without involving changes in genetic sequence. The best studied of these mechanisms are biochemical modifications, including changes in methylation of CpG dinucleotides and changes in histone acetylation or methylation.16
The normal pattern of epigenetic modifications in cells, the epigenome, arises during embryogenesis and development, and is inherited by daughter cells after mitosis of differentiated cells. However, temporary, reversible changes in epigenetic modification are essential for changes in chromosomal structure to allow, for example, transcription or DNA replication. But, some abnormal or prolonged changes to the epigenome can contribute to the development of cancer.
Although CpG dinucleotides are rare in the genome, clusters are often found in the promoter regions of genes. In general, promoter regions in normal cells are unmethylated. 17 But in cancer cells, hypermethylation of CpG clusters is common. 17
This hypermethylation causes transcriptional silencing of many tumour suppressor genes,18 including p16INK4a (involved in cell cycle control), p14ARF (a regulator of p53), hMLH1, BRCA1 and MGMT (DNA repair genes) and E-cadherin (involved in cell adhesion).
Recently, the epigenetic silencing of the DAPK1 gene has been identified as a cause of chronic lymphocytic leukaemia.19 Distinct patterns of methylation are seen in different human cancer types. 18 CpG methylation is carried out by DNA methyltransferase enzymes, which are often overexpressed in tumours. 18
Hypermethylation of CpG clusters has the potential to be used as a diagnostic tool for cancer, since this modification is rarely seen in normal cells.20 Understanding epigenetic changes also presents new opportunities for cancer treatment. For example, hypermethylation is potentially reversible, and the use of demethylating agents is currently being investigated. 21
Another important epigenetic mechanism in cancer involves biochemical modification of histone proteins, which have a primary role in controlling chromatin structure and gene expression. A characteristic change seen in many cancers is the loss of acetylation and methylation of histone H4.
However, unlike CpG cluster methylation, little is known about the patterns of histone modification seen in different types of human cancer. As with the DNA methyltransferases, the enzymes involved in histone modification are often dysregulated in cancers. 18
In the wake of completion of the human genome project, a similar mapping project for normal DNA methylation patterns has begun. The Human Epigenome Consortium first completed a pilot project looking at one region of chromosome 6.22 The pilot allowed the mapping techniques to be developed and validated prior to their use in mapping the methylation patterns of the entire genome.
Since the patterns are tissue-specific, the epigenome must be mapped in different tissues. An analysis of the methylation patterns of chromosomes 6, 20 and 22 in 12 different, normal tissues has recently been published.23
Other factors affecting cancer development
Although gene alterations are central to the disease process, the development of cancer is also influenced by an array of other cellular or local tissue environment factors.24 These include the activity of other genes within the cell that modify the effect of the mutated cancer genes; interactions with neighbouring cells; inflammatory and immune responses; and levels of circulating hormones or growth factors.24 Natural genetic variation in these factors is likely to be the source of some low-level predisposition to cancer (see Low-risk genetic polymorphisms).
For example, it has become apparent that several factors modify the risk of developing cancer associated with BRCA1 and BRCA2 mutations. The effect of other 'modifier' genes and non-genetic modifiers such as hormone levels may all contribute to the variation in risk between families and between different populations.25
The effects of genes also work in combination with lifestyle factors and choices, such as diet and smoking to affect an individual’s overall risk of developing cancer.
References
- Lander, E.S., et al., Initial sequencing and analysis of the human genome. Nature, 2001. 409(6822): p. 860-921
- The Cancer Genome Project, Wellcome Trust Sanger Institute.
- Vogelstein, B. and K.W. Kinzler, Cancer genes and the pathways they control. Nat Med, 2004. 10(8): p. 789-99
- Shtivelman, E., et al., Fused transcript of abl and bcr genes in chronic myelogenous leukaemia. Nature, 1985. 315(6020): p. 550-4
- Konopka, J.B., et al., Cell lines and clinical isolates derived from Ph1-positive chronic myelogenous leukemia patients express c-abl proteins with a common structural alteration. Proc Natl Acad Sci U S A, 1985. 82(6): p. 1810-4
- Knudson, A.G., Jr., Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A, 1971. 68(4): p. 820-3
- Santarosa, M. and A. Ashworth, >Haploinsufficiency for tumour suppressor genes: when you don't need to go all the way. Biochim Biophys Acta, 2004. 1654(2): p. 105-22
- Payne, S.R. and C.J. Kemp, Tumor suppressor genetics. Carcinogenesis, 2005. 26(12): p. 2031-45
- Sjoblom, T., et al., The consensus coding sequences of human breast and colorectal cancers. Science, 2006. 314(5797): p. 268-74
- Fearon, E.R. and B. Vogelstein, A genetic model for colorectal tumorigenesis. Cell, 1990. 61(5): p. 759-67
- Ilyas, M., et al., Genetic pathways in colorectal and other cancers. Eur J Cancer, 1999. 35(14): p. 1986-2002
- Vogelstein, B. and K.W. Kinzler, The multistep nature of cancer. Trends Genet, 1993. 9(4): p. 138-41
- Bjerkvig, R., et al., Opinion: the origin of the cancer stem cell: current controversies and new insights. Nat Rev Cancer, 2005. 5(11): p. 899-904
- Jordan, C.T., M.L. Guzman, and M. Noble, Cancer stem cells. N Engl J Med, 2006. 355(12): p. 1253-61
- Davies, H., et al., Mutations of the BRAF gene in human cancer. Nature, 2002. 417(6892): p. 949-54
- Esteller, M., Epigenetics provides a new generation of oncogenes and tumour-suppressor genes. Br J Cancer, 2006. 94(2): p. 179-83
- Jones, P.A. and S.B. Baylin, The fundamental role of epigenetic events in cancer. Nat Rev Genet, 2002. 3(6): p. 415-28
- Esteller, M., Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet, 2007. 8(4): p. 286-98
- Raval, A., et al., Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia. Cell, 2007. 129(5): p. 879-90
- Laird, P.W., The power and the promise of DNA methylation markers. Nat Rev Cancer, 2003. 3(4): p. 253-66
- Lyko, F. and R. Brown, DNA methyltransferase inhibitors and the development of epigenetic cancer therapies. J Natl Cancer Inst, 2005. 97(20): p. 1498-506
- Rakyan, V.K., et al., DNA methylation profiling of the human major histocompatibility complex: a pilot study for the human epigenome project. PLoS Biol, 2004. 2(12): p. e405
- Eckhardt, F., et al., DNA methylation profiling of human chromosomes 6, 20 and 22. Nat Genet, 2006. 38(12): p. 1378-85
- Ponder, B.A., Cancer genetics. Nature, 2001. 411(6835): p. 336-41
- Narod, S.A., Modifiers of risk of hereditary breast cancer. Oncogene, 2006. 25(43): p. 5832-6
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