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| Genetics of Cancer |
Only a small number of the approximately 35,000 genes in the human genome have been associated with cancer. (See the Genomics unit.) Alterations in the same gene often are associated with different forms of cancer. These malfunctioning genes can be broadly classified into three groups. The first group, called proto-oncogenes, produces protein products that normally enhance cell division or inhibit normal cell death. The mutated forms of these genes are called oncogenes. The second group, called tumor suppressors, makes proteins that normally prevent cell division or cause cell death. The third group contains DNA repair genes, which help prevent mutations that lead to cancer.
Proto-oncogenes and tumor suppressor genes work much like the accelerator and brakes of a car, respectively. The normal speed of a car can be maintained by controlled use of both the accelerator and the brake. Similarly, controlled cell growth is maintained by regulation of proto-oncogenes, which accelerate growth, and tumor suppressor genes, which slow cell growth. Mutations that produce oncogenes accelerate growth while those that affect tumor suppressors prevent the normal inhibition of growth. In either case, uncontrolled cell growth occurs.
Oncogenes and Signal Transduction
In normal cells, proto-oncogenes code for the proteins that send a signal to the nucleus to stimulate cell division. These signaling proteins act in a series of steps called signal transduction cascade or pathway (Fig. 1). (See the Genetics and Development unit.) This cascade includes a membrane receptor for the signal molecule, intermediary proteins that carry the signal through the cytoplasm, and transcription factors in the nucleus that activate the genes for cell division. In each step of the pathway, one factor or protein activates the next; however, some factors can activate more than one protein in the cell. Oncogenes are altered versions of the proto-oncogenes that code for these signaling molecules. The oncogenes activate the signaling cascade continuously, resulting in an increased production of factors that stimulate growth. For instance, MYC is a proto-oncogene that codes for a transcription factor. Mutations in MYC convert it into an oncogene associated with seventy percent of cancers. RAS is another oncogene that normally functions as an "on-off" switch in the signal cascade. Mutations in RAS cause the signaling pathway to remain "on," leading to uncontrolled cell growth. About thirty percent of tumors - including lung, colon, thyroid, and pancreatic carcinomas - have a mutation in RAS.
The conversion of a proto-oncogene to an oncogene may occur by mutation of the proto-oncogene, by rearrangement of genes in the chromosome that moves the proto-oncogene to a new location, or by an increase in the number of copies of the normal proto-oncogene. Sometimes a virus inserts its DNA in or near the proto-oncogene, causing it to become an oncogene. The result of any of these events is an altered form of the gene, which contributes to cancer. Think again of the analogy of the accelerator: mutations that convert proto-oncogenes into oncogenes result in an accelerator stuck to the floor, producing uncontrolled cell growth.
Most oncogenes are dominant mutations; a single copy of this gene is sufficient for expression of the growth trait. This is also a "gain of function" mutation because the cells with the mutant form of the protein have gained a new function not present in cells with the normal gene. If your car had two accelerators and one were stuck to the floor, the car would still go too fast, even if there were a second, perfectly functional accelerator. Similarly, one copy of an oncogene is sufficient to cause alterations in cell growth. The presence of an oncogene in a germ line cell (egg or sperm) results in an inherited predisposition for tumors in the offspring. However, a single oncogene is not usually sufficient to cause cancer, so inheritance of an oncogene does not necessarily result in cancer.
Tumor Suppressor Genes
The proteins made by tumor suppressor genes normally inhibit cell growth, preventing tumor formation. Mutations in these genes result in cells that no longer show normal inhibition of cell growth and division. The products of tumor suppressor genes may act at the cell membrane, in the cytoplasm, or in the nucleus. Mutations in these genes result in a loss of function (that is, the ability to inhibit cell growth) so they are usually recessive. This means that the trait is not expressed unless both copies of the normal gene are mutated. Using the analogy to a car, a mutation in a tumor suppressor gene acts much like a defective brake:if your car had two brakes and only one was defective, you could still stop the car.
How is it that both genes can become mutated? In some cases, the first mutation is already present in a germ line cell (egg or sperm); thus, all the cells in the individual inherit it. Because the mutation is recessive, the trait is not expressed. Later a mutation occurs in the second copy of the gene in a somatic cell. In that cell both copies of the gene are mutated and the cell develops uncontrolled growth. An example of this is hereditary retinoblastoma, a serious cancer of the retina that occurs in early childhood. When one parent carries a mutation in one copy of the RB tumor suppressor gene, it is transmitted to offspring with a fifty percent probability. About ninety percent of the offspring who receive the one mutated RB gene from a parent also develop a mutation in the second copy of RB, usually very early in life. These individuals then develop retinoblastoma. Not all cases of retinoblastoma are hereditary: it can also occur by mutation of both copies of RB in the somatic cell of the individual. Because retinoblasts are rapidly dividing cells and there are thousands of them, there is a high incidence of a mutation in the second copy of RB in individuals who inherited one mutated copy. This disease afflicts only young children because only individuals younger than about eight years old have retinoblasts. In adults, however, mutations in RB may lead to a predisposition to several other forms of cancer.
Three other cancers associated with defects in tumor suppressor genes include familial adenomatous polyposis of the colon (FPC), which results from mutations to both copies of the APC gene; hereditary breast cancer, resulting from mutations to both copies of BRCA2; and hereditary breast and ovarian cancer, resulting from mutations to both copies of BRCA1. While these examples suggest that heredity is an important factor in cancer, the majority of cancers are sporadic with no indication of a hereditary component. Cancers involving tumor suppressor genes are often hereditary because a parent may provide a germ line mutation in one copy of the gene. This may lead to a higher frequency of loss of both genes in the individual who inherits the mutated copy than in the general population. However, mutations in both copies of a tumor suppressor gene can occur in a somatic cell, so these cancers are not always hereditary. Somatic mutations that lead to loss of function of one or both copies of a tumor suppressor gene may be caused by environmental factors, so even these familial cancers may have an environmental component.
DNA Repair Genes
A third type of gene associated with cancer is the group involved in DNA repair and maintenance of chromosome structure. Environmental factors, such asionizing radiation, UV light, and chemicals, can damage DNA. Errors in DNA replication can also lead to mutations. Certain gene products repair damage to chromosomes, thereby minimizing mutations in the cell. When a DNA repair gene is mutated its product is no longer made, preventing DNA repair and allowing further mutations to accumulate in the cell. These mutations can increase the frequency of cancerous changes in a cell. A defect in a DNA repair gene called XP (Xeroderma pigmentosum) results in individuals who are very sensitive to UV light and have a thousand-fold increase in the incidence of all types of skin cancer. There are seven XP genes, whose products remove DNA damage caused by UV light and other carcinogens. Another example of a disease that is associated with loss of DNA repair is Bloom syndrome, an inherited disorder that leads to increased risk of cancer, lung disease, and diabetes. The mutated gene in Bloom syndrome, BLM, is required for maintaining the stable structure of chromosomes. Individuals with Bloom syndrome have a high frequency of chromosome breaks and interchanges, which can result in the activation of oncogenes.