II. Mutation and cancer.

III. Cancer progression.

Terms

Errata Page 341, last paragraph - page 342, first paragraph: Explanation is incorrect. See I.B. below. Figure 14.11 is correct, however.

I. Oncogenes are a class of genes that stimulate cell growth and division. Their modes of action are diverse. They function normally in the complex network of regulation of cell growth. Under abnormal circumstances, they may send inappropriate signals to the cell to grow.

A. Viral oncogenes were the first of this group to be recognized. They are introduced into a cell as part of a retroviral genome. These viral oncogenes originate as normal host genes (cellular oncogenes or c-oncogenes;proto-oncogenes) that, on very rare occasions, become incorporated into the viral genome during infection.
1. Retroviruses are very small RNA viruses, i.e. they store genetic information in the form of RNA rather than DNA. On invasion of a cell, the RNA is released into the cytoplasm, where a DNA copy is made by the process of reverse transcription. The enzyme that catalyzes this process, reverse transcriptase, is coded by the viral genome. The process is similar to transcription, in which RNA polymerase uses a DNA template to make an RNA copy. In this case, the reverse transcriptase uses an RNA template to make a DNA copy.

2. The DNA copy has the ability to insert itself into the host DNA, where transcription generates many more copies of the viral RNA.

3. On rare occasions, the virus may pick up a copy of a host gene, probably by inserting next to it. The host gene then becomes part of the viral genome. It now is transcribed in infected cells under the viral promoter rather than the normal host promoter that is tightly regulated by a network of transcription factors. The excess transcription of the oncogene causes infected cells to escape growth regulation. This can be a major factor in tumor development.

4. Such viruses are a very rare cause of human leukemia, but retroviruses are a common cause of feline and chicken leukemia.

5. A retrovirus can also insert its DNA near an oncogene, disrupting the regulation of that oncogene and causing excessive cell proliferation.

B. c-ras is an example of an oncogene whose action is well understood. The ras protein functions on the inner surface of the cell membrane as part of a signal transduction pathway that transmits signals from membrane receptors to the nucleus, which responds by cell growth and replication. The ras protein occurs in active and inactive forms. The inactive form is activated by the preceding component of the transduction pathway. The active form of ras then acts on the next component in the pathway. The active form is also self inactivating, shutting off the signal.
1. Mutations in ras can lock the protein in the active form by abolishing the self-inactivation activity. This causes continuous signals to the nucleus to divide.

2. High levels of normal ras protein also cause continuous cell growth and division.

C. Chromosome rearrangements, such as translocation, can place a cellular oncogene under control of the wrong promoter, leading to excess transcription of the oncogene. The various tissues have their characteristic active promoters, most genes being turned off. Therefore, only translocation breakpoints that involve these active promoters should cause a problem.
1. The abnormal white blood cells in chronic myelogenous leukemia typically have a translocation between chromosomes 9 and 22. The breakpoint in chromosome 22 is in the coding region of a gene called bcr. This breakpoint is joined to a breakpoint on chromosome 9 in the coding region of an oncogene called abl. The fusion gene is under control of the bcr promoter, which is active in these cells, and contains the beginning of the bcr coding region, ending with the active region of the abl gene. This fusion protein provides continuous instructions for the cells to proliferate. The translocation occurs only in the leukemic cells, the normal white cells and other somatic cells of the body being chromosomally normal.

2. A similar situation occurs in the case of Burkitt lymphoma. The myc oncogene on chromosome 8 is placed under control of one of the promoters on chromosomes 2, 14, or 22 that controls production of antibody proteins. The normal function of this cell type is to make antibodies. Instead, they make the oncogene product.

D. Another mechanism for generating excess oncogene product is gene amplification. For reasons not understood, a particular chromosome segment may form a very large number of tandem copies. This presumably happens very rarely, and in most cases the cell probably does not survive. However, if the tandemly repeated element includes an oncogene, excessive transcription may result.

A. In order to contribute to the development of cancer, the locus in which the mutation occurs must be active in the tissue in which the mutated locus arises. There are probably some exceptions to this. For example, the mutation may interrupt the process that causes a locus to be inactive. As a general rule, however, the mutations that contribute to cancer are in genes that are active. An example is the high frequency of chromosome translocation breakpoints on chromosomes 2, 7, 14, and 22 in leukemias and lymphomas at the sites of the genes that are important in immunity. Each type of tissue has an array of loci in which mutations can cause cancer risk. Mutations in some loci contribute to cancer in many tissues; mutations in other loci contribute to cancer only in one or a few tissues.

B. The number of mutations required for development of cancer varies with the cancer type. In the case of retinoblastoma, only the two mutations at the single RB locus are sufficient if they occur in a retinoblast cell. RB mutations contribute to other cancers also in other tissues, but other loci must mutate as well.

C. Since the accumulation of mutations at specific loci is essential in development of cancer, it follows that anything that increases the mutation rate in somatic cells is carcinogenic.

1. Many chemicals in the environment are both carcinogenic and mutagenic. Perhaps the most common is tobacco smoke. A general rule is that mutagens are also carcinogens, although there are some exceptions.

2. Ultraviolet radiation, X-rays, and other forms of high-energy radiation are both carcinogenic and mutagenic.

3. Inherited deficiencies in DNA repair systems are associated with increased mutation and with cancer.

a. An example is xeroderma pigmentosum, discussed earlier. Persons homozygous for XP cannot repair damage caused by ultraviolet light.

b. Another example is hereditary nonpolyposis cancer of the colon, a dominantly inherited form of colon cancer. The inherited defect is in DNA repair, which greatly increases the mutation rate at all loci. Once a mutation occurs in a HNPCC gene, then the necessary additional mutations at other loci are much more likely to occur.

c. A third important example is ataxia telangiectasia, a recessively inherited disorder associated with chromosome instability. In this case, heterozygotes, who are otherwise normal phenotypically, appear to have increased risk of cancer, especially breast cancer, for which the risk is about 5% in heterozygous women.

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