The Genetics of Cancer
Dr. Jay D. Hunt, III
For many families in southern Louisiana, cancer has become a common condition. Cancer strikes about one in every three Americans, so all of us have loved ones who have suffered from this disease. I very often receive calls from concerned friends and relatives who have been diagnosed with cancer or who have had a close friend or loved one diagnosed. The most common questions are "What is cancer?" and "How did I get it?"
WHAT IS CANCER?
Cancer is a disease of cells. The body is made up of a community of individual cells, each of which has a specific job to ensure that the community functions correctly. Liver cells must detoxify the fluids of the body, lung cells must exchange oxygen and carbon dioxide from the blood, and skin cells must separate the outside world from the inside of our body.
In addition to performing their assigned jobs, cells are also good citizens. Cells respect the space of the other cells around them and support the healthiness of those cells. Occasionally, cells begin to grow in an uncontrolled fashion, causing many problems for the body. Cancer is a disease of uncontrolled cell growth (or proliferation). Cancer cells are no longer good citizens. For instance, a liver cell that becomes cancerous no longer does its job of detoxifying the body. In addition, cancer cells do not respect their neighboring cells and will crowd them out of existence. Cancer cells push normal cells out of the way and use up all of the nutrients in the body to fuel their own uncontrolled growth. A group of cancer cells in the body is often called a tumor (a swelling), but not all tumors are cancerous. This concept is illustrated in Figure 1. Tumors are classified as benign or malignant. Benign tumors typically do not threaten the life of the patient, although this is not always the case. Benign tumors that develop in the brain can cause serious health effects or even death because the brain is contained within the skull. As the benign tumor expands, the normal brain has no place to go to get out of the way and can be damaged by the expanding benign tumor. Malignant tumors (or cancer) are always serious and will often lead to death if not treated promptly. Malignant tumors often spread to other organs (or metastasize).
Fig. 1. The steps involved in the formation of colon cancer or rectal cancer are shown. Cancer is a disease of cells. In the first drawing (labeled "normal"), note that each of the normal cells are about the same size, are organized in a orderly fashion, and are all on top of a basement membrane that separates these cells from other types of cells and from cells of different organs of the body. At some time, a normal cell develops enough mutations that it begins to grow slightly faster than the cells around it (the reddish cell in the center of the second drawing, labeled "single hyperproliferative cell"). Hyperproliferative means the cell grows faster than normal cells. When enough hyperproliferative cells accumulate, a small benign tumor called an adenoma develops (third drawing). During a colonoscopy, the doctor is looking for such adenomas. If an adenoma is removed at this stage, the patient will be fine and a cancer will not develop from this particular group of cells. Note two things about the adenoma in the third drawing: (1) the cells are starting to pile up on one another and that they are not organized like normal cells, and (2) the cells are still on one side the basement membrane. If the adenoma is allowed to remain in the patient for many years, a cancerous tumor (called a carcinoma) will form inside of the adenoma. The cells in this carcinoma break through the basement membrane and will spread inside the colon, eventually leaving the colon to spread to other organs like the liver. In the fourth drawing, a tumor cell can be seen in the lower right hand corner breaking into a small blood vessel (pink segmented circle). Cancer cells often use body fluids like the bloodstream to spread or metastasize.
Ultimately, it is this lack of respect for the body by cancer cells that dooms a person to death. To return to our example of liver cancer, the cancerous liver cells do not perform the job of the liver and destroy the normal liver cells around them by their lack of respect for those cells. In the end, the person is left without a functional liver and dies of liver failure.
Cancer is many different diseases. Cancer is not one disease,but literally hundreds of different diseases. This is of great practical importance to both physicians and patients, because different cancers are treated differently and have different outcomes for the patient. For instance, breast cancer is different from brain cancer: If caught early, breast cancer is a very treatable disease and patients can look forward to a cure and a normal life expectancy. On the other hand, brain cancer is an extremely aggressive disease, and the outcome is usually poor, regardless of how early the cancer is detected. Furthermore, brain cancer itself is not one disease but many diseases, each with different potential outcomes and treatments. In fact, if not caught early, breast cancer very often spreads (metastasizes) to the brain, and the breast tumor grows in the brain. Ultimately, for a typically non-aggressive disease like breast cancer, it is the spread of the tumor to a vital organ like the brain that causes illness and death.
HOW DID I GET CANCER?
Cancer is a genetic disease. Cancer is a genetic disease. This should not be confused with the statement that cancer is a hereditary disease. The two statements are profoundly different. A hereditary disease is one that is passed from the parents to a child through the inheritance of a defective gene. Although in some rare instances, such as retinoblastoma (a rare childhood tumor of the eye), cancer is hereditary, this is the exception rather than the rule. Most cancers are not obviously hereditary, although for certain cancers, like breast cancer, there may be a hereditary component to the disease (a "susceptibility"). However, all cancers are genetic, meaning that they result from the unnatural function of one or more genes.
Cancer forms when genes within
a normal cell are damaged and mutated. Mutations
in DNA can occur for many reasons. Cigarette smoke
contains chemicals that will damage DNA. Solar
radiation from the sun contains ultraviolet (or
UV) rays that will damage DNA. In most instances,
the DNA damage will not lead to cancer or other
diseases. But in some cases the damaged DNA does
lead to cancer. There are about 35,000 genes in
each human cell, but, in most cases, a mutation
within a gene will not lead to the development
of cancer. It is only when mutations occur in certain
key genes that cancer develops. These key genes
can be grouped into three classes:
Multiple genes are defective in cancers. Cancer does not occur from a single gene mutation in a single gene. Instead, the development of cancer involves multiple mutations within several key genes, including mutations in proto-oncogenes, tumor suppressor genes, and DNA repair genes (Figure 2). The process of accumulating mutations in several genes like this normally takes many years, and this is why cancer is more frequently seen in older individuals.
Fig. 2. Several mutations must occur in the DNA of an individual cell for cancer to develop. Normal cells (light gray) from one of the body's organs may develop mutations that allow them to grow slightly faster than the cells around them. These mutated cells (light blue) are not tumor cells yet, because they must undergo further mutations before cancer can form. Cells developed from these light blue mutated cells form a "larger" target for future mutations, because they grow slightly faster than the cells around them and because they already have at least one mutation on the way to forming cancer. Finally, when enough mutations are accumulated, cells (dark blue) form a tumor. The tumor cells are not yet malignant but will soon be if left untreated. Tumor cells develop further mutations and then change into malignant cancer cells (red). Malignant cells form a cancer at the original organ. These malignant cancer cells will develop still more mutations and then will spread (metastasize) to other organs through the bloodstream.
How key genes become defective. The answer to the question "How did I get cancer?" is very often difficult to address. For those who smoke cigarettes and develop lung cancer, the answer is clear: The chemicals in the cigarette smoke caused mutations in key genes in the cells of your lungs and led to the formation of lung cancer. If you had never smoked, or if you had quit smoking at an early age, you probably would not have developed lung cancer. However, for a young woman who exercises and eats correctly but who develops breast cancer at age 41, the question is much more difficult to answer in an acceptable fashion. We know that mutations occurred in key genes in the cells of her breast, but identifying the source of those mutations is often impossible. The newly diagnosed woman is likely to ask, "What did I do to cause this? What could I have done differently to avoid my cancer?" The answers to these questions remain largely unknown. In some instances, we know that having a mother or sister who developed breast cancer at a young age puts a woman at an elevated risk for also developing breast cancer at an early age. In this case, breast cancer is not only genetic, but there is also a hereditary component to the disease. For breast cancer, the best we can say at this time is this: If you are at elevated risk for breast cancer, talk to your doctor about setting up a screening program with routine examinations.
Fig. 3. The chemicals in cigarette smoke cause mutations in key genes. In the top portion of the figure is the DNA molecule. DNA is composed of four bases represented by A, C, G, and T. In this figure, A's are color coded by white, C's by green, G's by red, and T's by blue. DNA is read by the cell and used as a recipe to produce protein shown by the blue cubes. When someone smokes, mutations can occur in the DNA molecule and some of the bases change. In this example, a G is mutated to a T. This causes the protein in the lower panel to be made incorrectly, and such a defective protein may not perform its intended job properly.
DOES THE ENVIRONMENT CONTRIBUTE
TO MY CHANCES OF DEVELOPING CANCER?
Many of Louisiana's residents have a love-hate relationship with the petrochemical industry. On one hand, the many chemical plants in the river parishes provide much valued employment and contribute to the development of the society. On the other hand, many of the chemicals produced by the plants are known or suspected carcinogens, and many residents fear that the plant that puts food on the table by employing their family members may also be making their family members sick.
Environmental risks for developing cancer. We predict that as many as 80% of cancers may be attributable to environmental risk factors. The major environmental risk factors are listed below:
Among these risk factors, the use of tobacco (cigarette, cigar, pipe, or smokeless tobacco), unhealthy diet (rich in fatty foods), and physical inactivity (leading to obesity) are more likely to increase a person's cancer risk than the very low levels of pollutants in food, drinking water, and air. However, the risk from these pollutants increases with larger concentrations and longer duration of exposure. For instance, significant increases in cancer risk are associated with workers that have been exposed to high concentrations of ionizing radiation, certain chemicals, metals, and other substances (see Table I, below). Fortunately, industrial pollution has not had a major effect on cancer incidence. These pollutants are present in the environment at very low levels, and it does not seem likely that they are a major contributor to total cancer incidence.
The major risks are easily controllable. Luckily, the environmental risk factors that most significantly contribute to cancer risk are those that we as individuals can do something about. The use of tobacco causes about 30% of all cancer deaths. It is by far the major identified cause of human cancer. By stopping smoking, a person substantially reduces the risk of cancer. After about 20 years of not smoking, the risk of lung cancer for an ex-smoker is about the same to that for a non-smoker-and about ten times less than if smoking had continued. Diet is also a major risk factor for cancer that can be controlled. Obesity increases the risk of breast cancer (in post-menopausal women), colon cancer, endometrial cancer (uterine corpus cancer), prostate cancer, uterine cervical cancer, ovarian cancer, and cancer of the gallbladder. The relative risk of breast cancer in post-menopausal women is 50% higher for the obese. The relative risk for colon cancer in men is 40% higher for the obese. The relative risks of gallbladder and endometrial cancer are five times higher for obese individuals compared with individuals with a healthy weight. Other studies have also shown a possible association between obesity and cancers of the kidney, pancreas, rectum, esophagus, and liver.
Use of cellular phones is NOT an environmental risk for cancer. Finally, types of questions that are often asked today are: Do cell phones cause cancer?" "Can I get cancer from living underneath power lines?" Cell phones use radio waves, a very low-energy form of radiation, to transmit signals between caller and receiver. In addition, they generate very low-energy "power frequency" radiation, just as household appliances and electrical wires. Low-energy radiation like radio waves, power frequency radiation, radar, and microwaves, have not been proven to cause cancer. Some early studies suggested that these forms of radiation were associated with cancer, but most of the new, more extensive research in this area does not suggest an association. The answer to the question is "No": Cellular phones do not cause brain cancer and living under power lines does not cause leukemia or any other kind of cancer.
Although these low-energy forms
of radiation do not cause cancer, exposure to high-energy
radiation, like X-rays and ultraviolet radiation,
is a cancer risk. For this reason, a person's exposure
to ultraviolet rays from the sun or from tanning
booths (despite how safe tanning booths claim to
be) should be limited to short exposures. The X-rays
a person receives in the hospital or clinic when
X-rays are being taken is not only of a short exposure
but is also of a safe level of energy. For this
reason, there is virtually no risk of developing
cancer from medical X-rays.
Table1. Occupational Carcinogens
|4-aminobiphenyl||Chemical and dye workers||Bladder|
|Arsenic||Mining, pesticide workers||Lung, skin, and liver|
|Benzene||Leather, petroleum, rubber, and chemical workers||Leukemia|
|Benzidene||Chemical, dye, and rubber workers||Bladder|
|Bis (chloromethyl) ether||Chemical workers||Lung|
|Chromium||Metal workers, electroplaters||Lung|
|Isopropyl alcohol||Manufacturing by strong acid process||Lung|
|Leather dust||Boot and shoe manufacturing and repair||Nasal and bladder|
|Mustard gas||Mustard gas workers||Lung, larynx, and nasal|
|Naphthylamine||Chemical, dye, and rubber workers||Bladder|
|Nickel dust||Nickel refining||Nasal and lung|
|Soots, tars, and oils||Coal, gas, and petroleum workers||Lung, skin, and bladder|
|Vinyl chloride||Rubber workers, polyvinyl chloride manufacturing||Liver|
|Wood dusts||Furniture manufacturing||Nasal|
It is important to understand that cancer is a genetic disease. For most types of cancer, the mutations that occur in the genes of the cancer cell are caused by exposures to environmental factors that are controllable. Typically, these controls are easy to understand as well: quit smoking, use sunscreen, eat a lot of fresh fruits and vegetables, and lose weight through proper diet and exercise. We have made great strides in our understanding of the genetics of cancer in the last 30 years. Early pioneers in the cancer field discovered that certain viruses could cause cancers in experimental animals. Later, geneticists discovered that the genes that cause cancer are mutated versions of normal genes found in healthy cells. Finally, we have started to experiment with the repair of defective genes through a process known as gene therapy. For the patient, all of this new genetic information about cancer promises to lead to both better advice for avoiding cancer and better treatments for those who develop cancer.
HOW TO LEARN MORE
Jay D. Hunt, III, Ph.D., is Associate Professor of Biochemistry and Molecular Biology, Stanley S. Scott Cancer Center, LSU Health Sciences Center at New Orleans and Adjunct Associate Professor of Biochemistry, Tulane University Health Sciences Center in New Orleans. His research involves finding the specific gene defects that lead to cancers.
CONTACT THE AUTHOR
Jay D. Hunt, III, Ph.D.
LSU Health Sciences Center
Department of Biochemistry and Molecular Biology
533 Bolivar Street, CSB-4-18
New Orleans, LA 70112