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Cancers are the result of genetic mutations that may be caused by any number of factors. For example, repeated exposure to certain types of radiation or certain harmful chemicals may trigger a single genetic mutation, which, when multiplied over many generations of cells, results in cancer. In this section, we will discuss the different types of genetic mutations which may lead to cancer and the different types of agents which may cause these genetic mutations.
Each of your genes is comprised of a piece of DNA, which is composed of two chemical strands twisted around each other to form a double helix. Each strand of DNA is constructed from millions of chemical building blocks called bases. These bases (there are only four, abbreviated A, T, G, and C), may be arranged in any sequence. The sequence of bases in any given gene determines the message that gene contains, just like the letters of the alphabet are combined in different ways to form words and sentences. These genetic sentences are the instructions (coding) every cell in your body needs to build the proteins it requires to function. One gene codes for one protein. Image 1 illustrates the structure of DNA.
|Image 1: Structure of DNA|
Mutations are changes in the composition of a gene, and may occur in one of several ways. The simplest type of mutation involves a change in a single base along the sequence of a particular gene—much like a spelling error in a word. In other cases, one or more bases may be added or deleted. Sometimes, large segments of a DNA molecule are accidentally repeated, deleted, or moved.
Like normal genes, mutated genes direct the production of various proteins that control a cell's behavior. Sometimes these proteins control other genes by turning them on or off, thus resulting in changes in the way a cell functions or reproduces itself. In the mutated cell, these proteins are often structurally altered or overexpressed. These changes in protein production are thought to be responsible for many of the characteristics of the cancer cell, such as uncontrolled cellular growth or loss of contact inhibition. They may also affect the cell’s sensitivity to chemotherapy or radiation.
There are two general categories of genetic mutations:
- Hereditary mutations
- Acquired mutations
Hereditary mutations are inherited from your parents, and therefore, exist in virtually all the cells of your body. Hereditary mutations are passed down from generation to generation and are thought to be the cause of only a small percentage of cancers. In general, cancer is not considered an inherited disease because 80% to 90% of cancers occur in people with no significant family history of cancer. The presence of a particular genetic mutation linked to cancer does not guarantee that you will get that cancer, but it may increase your risk substantially. For example, about 5% of breast cancers are thought to be due to inheritance of one or more breast cancer susceptibility genes (so called BRCA mutations) passed from one generation to the next. You will learn more about the genetic causes of cancer later in this section.
Acquired mutations occur when the DNA in a cell changes during a person’s lifetime. This may be caused by exposure to environmental factors ( carcinogens ) such as radiation or toxic chemicals, or perhaps, even as a result of the aging process. Because these mutations are not hereditary, they cannot be passed down from generation to generation. You will learn more about the various environmental causes of cancer later in this section.
Mutagenesis refers to the process whereby genes become mutated. Mutations may be caused by DNA-damaging agents, such as cigarette by-products and radiation. They may also be caused by spontaneous errors that occur during the DNA replication that precedes cell division.
For example, as you learned earlier, growth factors and growth inhibitory factors play important roles in cell growth regulation. If a genetic mutation occurs during DNA replication that either disrupts the production of a particular growth factor, or decreases a cell’s sensitivity to it, the balance between cell production and apoptosis is disrupted. This type of genetic mutation is, in effect, changing the cell’s rate of division by altering the number or behavior of the proteins responsible for the growth-regulating factors.
There are three major categories of cancer-causing gene mutations:
- Tumor suppressor genes
- DNA repair genes
Oncogenes are abnormal forms of the genes that regulate cell growth. Oncogenes contribute to the development of cancer by instructing cells to make proteins that stimulate excessive cell growth and division. A gene called the ras gene, for example, is responsible for producing the ras protein. The ras protein regulates cell division. In healthy cells, the ras gene is usually inactive and does not trigger the production of the ras protein. In cancerous cells, however, the gene is activated (due to acquired mutations) and signals cells to divide even when they should not. In approximately 25% of all cancers, the ras gene is mutated.
Another example of oncogene activity involves their production of protein kinases , enzymes that help regulate many cellular activities, including the initiation of cell division. Several types of cancer (eg, bladder cancer, breast cancer, chronic myelocytic leukemia [CML]) contain structurally altered protein kinase enzymes. When overproduced or altered, the kinases stimulate continuous cell division. Image 2 illustrates the differences between normal genes and oncogenes.
|Image 2: Oncogenes|
By producing abnormal versions or quantities of cellular growth factors, oncogenes cause a cell's growth-signaling pathway to become hyperactive. It may be helpful to think of the growth-control pathway as being similar to the gas pedal in your car. The presence of an oncogene is like having your gas pedal stuck to the floorboard, causing the cell to continually grow and divide.
Tumor suppressor genes are normal genes whose absence can lead to cancer. Normally, tumor suppressor genes instruct cells to produce proteins that restrain cell growth and division. Since tumor suppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in an uncontrolled fashion. You can think of tumor suppressor genes as being like the brake pedal on your car. The loss of a tumor suppressor gene function is like having no brakes because it allows cells to grow and divide continually. Image 3 illustrates the differences between normal genes and tumor suppressor genes.
|Image 3: Differences between tumor suppressor genes and normal genes|
One particular tumor suppressor gene codes for a protein called p53 that can trigger apoptosis (the proper death of cells). In cells that have undergone DNA damage, the p53 protein acts like a brake pedal and halts cell growth and division. If the damage cannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cell from growing out of control. Mutated p53 genes allow cells with abnormal DNA to survive and divide. The mutations are passed on to the daughter cells during the process of cell division, increasing the risk of developing cancer. The p53 gene is defective in most cancers.
DNA repair genes code for proteins that normally function to correct errors that inevitably occur during DNA replication. Mutations in DNA repair genes may lead to an inability to repair defective DNA, which in turn may allow subsequent mutations in tumor suppressor genes and oncogenes to multiply. People with a condition called xeroderma pigmentosum , for example, have an inherited defect in a DNA repair gene. As a result, they cannot effectively repair the DNA damage that normally occurs when skin cells are exposed to sunlight. People with this condition, therefore, have abnormally high rates of skin cancer due to an abnormally high rate of uncorrected DNA damage. Certain forms of hereditary colon cancer also involve defects in DNA repair. Image 4 illustrates the effects of DNA repair genes.
|Image 4: DNA Repair Genes|
Cancer rarely involves a single mutation. Researchers believe that most cancers result from an accumulation of mutations involving oncogenes, tumor suppressor genes, and DNA repair genes. According to this theory, cancer cells are successfully created only when the brakes (tumor suppressor genes) are released just as the accelerators (oncogenes) are pressed, and all while the mechanic is unavailable to repair the damaged parts.
In addition, since cancer cells are especially prone to genetic defects, each successive generation of rapidly dividing cells tends to produce additional mutations. During the time it takes a single transformed cell to proliferate into an identifiable tumor (about a billion cells), an enormous number of genetic mutations have produced a highly varied mass of abnormal cells. Image 5 illustrates how multiple mutations may eventually lead to cancerous tumor.
|Image 5: Tumor Suppressor Genes and cell growth and division|
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- Reviewer: Igor Puzanov, MD
- Review Date: 09/2012
- Update Date: 09/26/2012