Cancer and genetics

SIGNIFICANCE: At its root, cancer is a genetic disease. It is characterized by unrestrained growth and reproduction of cells, loss of contact inhibition, and, eventually, metastasis (the wandering of cancer cells from a primary tumor to other parts of the body). All of these changes represent underlying mutations or inappropriate expression of genes involved in controlling the cell cycle and related processes.

The Problem of Cancer

Cancer is characterized by abnormal cell growth that leads to the invasion and destruction of healthy tissue by cells that meet certain criteria. Normal cells in the human body are continuously growing but are under normal cell control mechanisms. Cancer cells begin as normal cells that, as a result of genetic mutations, start to grow uncontrollably, escaping from the normal rules regulating cell growth and behavior. Cancer cells are characterized by six traits that differentiate them from normal healthy cells: cells that grow to abnormally large size; disregard for normal growth signals; lack of sensitivity to growth inhibition factors (antigrowth signals); avoidance of natural cell death (apoptosis); uninhibited replication; ability to form new vascular supply (angiogenesis); and ability for metastasis and invasion of neighboring tissues. Contact inhibition, in which cells contacting other cells prevent unrestrained growth, is lost in cancer cells. Normal cells also remain in one location, or at least in the same tissue, but malignant tumors, in their later stages, metastasize, allowing their cells to wander freely in the body, leading to the development of tumors in other organs. A final common feature is that cancer cells lose their normal cell shape.

The area where cancer begins to form a tumor is called the primary site. Most types of cancer begin in one place (the breast, lung, or bowel, for example), from which the cells invade neighboring areas and form secondary tumors. To make matters more complicated, some types of cancer, such as leukemia, lymphoma, and myeloma, begin in several places at the same time, usually in the bone marrow or lymph nodes. Primary tumors begin with one abnormal cell. This cell, as is true of all cells, is extremely small, no more than 0.002 or 0.003 millimeters across (about one-twentieth the width of a human hair). Therefore, early cancer is very difficult to locate. Even if there are more than 100,000 cancer cells in a tumor, it is barely visible except under a microscope.

In general, cancer cells divide and reproduce about every two to six weeks, although different types of cancer grow at different rates. If they divide once per month on average, a single cell will multiply into approximately four thousand cells by the end of a year. After twenty months, there will be one million cells, which would form a tumor about the size of a pinhead and would still be undetectable. A tumor can be discovered only when a lump of approximately one billion cells is present. This would be about the size of a small grape. It would take about two and one-half years for a single cancer cell to reach this size. Within seven months, the one billion cells would grow to more than 100 billion cells, and the tumor would weigh about four ounces. By the fortieth month of growth, the lump of cancer cells would weigh about two pounds. By the time a tumor has reached this size, death often occurs. Death normally occurs about three and one-half years after the first cancer cell begins to grow. It takes about forty-two cell doublings to reach the lethal stage. The problem is that, in most cases, tumors are detectable only after thirty doublings. By this time, cancer cells may have invaded many other areas of the body beyond the primary site.

How Cancer Cells Grow and Invade

Cancer cells are able to break down the barriers that normally keep cells from invading other groups of cells. With the aid of a microscope, cancer cells can be observed breaking through the boundary between cells, called the basement membrane. Cancer cells can make substances that break down the intercellular matrix, the “glue” that holds cells together. The intercellular matrix is a complex mixture of substances, including collagen, a strong, fibrous protein that gives strength to tissues. Cancer cells produce collagenase, an that breaks down collagen. Cancer cells also produce hyaluronidase, which further breaks down the intercellular matrix. This causes cancer cells to lose their normal shape and allows them to push through normal boundaries and establish themselves in surrounding tissues. Cancer cells have jagged edges, are irregular in shape, have large nuclei, and have hard-to-detect borders, making them relatively easy to identify microscopically. Normal cells, on the other hand, have a regular, smooth edge and shape.

There are many steps involved in the process of metastasizing, not all of which are understood by researchers. First is the entry into a blood vessel or lymph channel. Lymph channels, or lymphatics, comprise a network of vessels that carry lymph from the tissues to the bloodstream. Lymph is a colorless liquid that drains from spaces between cells. It consists mainly of water, salts, and proteins and eventually enters the bloodstream near the heart. The function of lymph is to filter out bacteria and other foreign particles that might enter the blood and cause infections. A mass of lymph vessels is called a lymph node. In the human body, lymph nodes are found in the neck, under the arms, and in several other places. Every body tissue has a network of lymph and blood vessels running through it.

Once a malignant tumor develops and metastasizes, the cells often travel through the body using the lymphatic system, a network of vessels that filter pathogens and transport lymph, a fluid similar to blood plasma. Cancer cells may gain entry into a nearby lymph vessel by breaking down defensive enzymes. Once in the lymph system, they can travel to nodes (glandlike masses of cells that produce white blood cells) and eventually into the bloodstream. Whatever route they take, groups of cancer cells can break away from the primary site of the tumor and float along whatever vessel they have invaded, forming numerous secondary tumors along the way. Because cancer cells are not considered foreign substances, such as bacteria or viruses, they are able to evade the body’s immune system. Because of their overall resemblance to normal cells, cancer cells fool the body into thinking they are normal and therefore not dangerous.

Cancer cells eventually enter narrow blood vessels called capillaries and stay there for a brief period before they enter tissues such as lungs, bones, skin, and muscle. The secondary tumors then capture their own territory. As a tumor establishes itself, its cells often secrete signal proteins that stimulate new blood vessels to form (a process called angiogenesis) to increase blood supply to the growing tumor. The body thus not only fails to destroy developing tumors but also unwittingly helps establish them.

The Genetics of Cancer

Cancer has been known since antiquity, but it was not until the twentieth century that the underlying causes of cancer began to be explored. In 1910, Peyton Rous discovered a type of cancer in chickens called a sarcoma (a cancer of connective tissue) that could be passed on to other chickens. He demonstrated this by removing tumors from affected chickens, grinding the tumors up, filtering the grindate, and then injecting the filtrate into healthy chickens. Injected chickens invariably developed sarcoma tumors, suggesting that something smaller than the tumor cells was being passed on and was stimulating cancer development in otherwise normal cells. It is now known that the filtrate contained a cancer-causing virus, now called the Rous sarcoma virus. Similar types of viruses were discovered to be responsible for cancers in a variety of animals, but none was discovered in humans initially.

As the genetic material of some of the tumor viruses was later analyzed, all of them were discovered to contain genes called oncogenes because they promoted oncogenesis (tumor development). Even more surprising was the discovery that humans have genes in their genome that are homologous (having a high degree of similarity) to viral oncogenes. The human genes did not seem to cause cancer under normal circumstances and were called proto-oncogenes. In cancer cells, some of these proto-oncogenes were discovered to have mutations or, in some cases, were simply overexpressed. In recognition of their abnormal state, these genes were called cellular oncogenes to distinguish them from viral oncogenes. It is now known that proto-oncogenes are important in controlling the cell cycle by stimulating cell division only at the appropriate time. When they are transformed into oncogenes, uncontrolled cell growth and division, two of the hallmarks of cancer, occur.

A second type of cancer-causing gene, called a tumor suppressor gene, was discovered to be the cause of retinoblastoma, a cancer of the retina, most often occurring in children. Tumor suppressor genes have an effect opposite to that of proto-oncogenes; they suppress cell division and thus prevent unrestrained cell proliferation. If both alleles of a tumor suppressor gene have a mutation that makes them nonfunctional, then cell division can occur unchecked. Retinoblastoma occurs in children when they inherit one faulty copy from a parent. If the other copy experiences a mutation, which frequently occurs, then retinoblastoma develops.

How Cancer Develops

The development of cancer is typically more complicated than implied above. Information gathered from the Human Genome Project helped improve our understanding of the role of genetics and genetic mutations not only in the development of cancer but also in its treatment. The development of cancer generally requires mutations in more than a single proto-oncogene or tumor suppressor gene. Any factors that increase mutation rates or decrease the ability of a cell to repair mutations will increase the likelihood that cancer will develop. Inheritance of already mutated genes can also greatly increase a person’s chance of developing cancer, which accounts for the above-normal occurrence of certain types of cancer in some families.

One of the best-studied cases of oncogenesis involves colorectal cancer, which takes years to develop from a small cluster of abnormal cells into life-threatening cancer. It involves the loss or mutation of three tumor suppressor genes and one proto-oncogene. Often, colorectal cancer runs in families because the loss of the first gene, the APC tumor suppressor gene, is often inherited, resulting in an increased chance of developing the disease. Loss of this gene causes increased cell growth and some other genetic changes. In the next step, the Ras oncogene is mutated, causing even more cell growth. Two more tumor-suppressor genes are lost, DCC and p53, at which point a tumor called a carcinoma has developed. Additional gene loss, which occurs much more easily in tumor cells, leads to metastasis, and the cancer then spreads to other organs and tissues.

Mutations in the BRCA1 and BRCA2 genes are responsible for up to half of all cases of breast cancer in women with a family history of the disease. Furthermore, the presence of such mutations helps guide treatment choices, with some women voluntarily undergoing prophylactic mastectomy if they have a family history of the genetic mutation. Although the identification of the BRCA1 and BRCA2 genes may help assess a woman’s risk for developing breast cancer, it is important to note that it is not a definitive test. Women who have the mutation may never develop cancer, and breast cancer may develop in women who do not have these mutations. While researchers hoped that further study would lead to the discovery of more individual genes clearly linked to specific forms of cancer like BRCA1 and BRCA2, as of 2024 this had not happened, and research suggested that most cancers were linked to more complex combinations of multiple genes that would require larger studies to identify. Researchers have, however, identified some genes, like PALB2, PTEN, and TP53, that may increase a person's liklihood of developing breast cancer or other forms of cancer if they have mutations.

Inheritance of a gene loss or mutation does not mean a person will get cancer; it simply means they have a higher chance of developing cancer. Although the development of cancer is ultimately genetically based, environmental factors also play a part. In the case of colorectal cancer, a diet low in roughage is often considered to increase colorectal cancer rates. Exposure to carcinogens, chemicals, or other factors, such as radiation, can also increase the likelihood of cancer. Exposure can occur as a result of diet, skin exposure, or inhalation. For example, smoking cigarettes is known to increase the occurrence of lung cancer as well as a variety of other cancers. Excess exposure to damaging UV rays in sunlight or other sources is known to significantly increase the occurrence of skin cancer. Carcinogens promote cancer because they cause damage to DNA, and if the damage happens to occur to a tumor-suppressor gene or oncogene, then cancer may occur.

Inheritance of some mutations is particularly potent in increasing the chances of developing cancer. One example is the genetic disease xeroderma pigmentosa. Individuals with this disease develop skin cancer in response to even relatively brief exposure to UV radiation and must therefore avoid exposure to sunlight. In these types of highly heritable cancers, it appears that the mutations cause some kind of deficiency in the cellular DNA repair systems. As a result of a decreased ability to repair mutations, it is just a matter of time before mutations occur in proto-oncogenes or tumor-suppressor genes, so the only way to prevent cancer is to control exposure to as many environmental carcinogens as possible and to aggressively screen for tumors.

Cancer Treatment

Cancers vary in their severity and rate of growth, which means that proper treatment depends on correctly diagnosing the type of cancer. For example, some forms of prostate cancer grow extremely slowly, and metastasis is rare until very late stages in the disease, sometimes many years after initial diagnosis. Treatment may comprise simply monitoring the tumor, avoiding carcinogenic exposure as much as possible, and possibly changing one’s lifestyle. On the other hand, some types of skin cancer progress so rapidly that aggressive treatment may be required, unless it is caught very early. Although survival rates for many types of cancer have risen, treatment for most cancers is still only partially successful, and the later a tumor is detected, the greater chance that it will be untreatable.

New therapies are constantly being developed, but most cancers are still treated using surgery (removal of tumors), chemotherapy, and radiation therapy, either singly or, more often, in combination. More important than the specific treatment used is detecting tumors in their earliest stages, before they have extensively invaded surrounding tissues or metastasized. Survival rates are high for most cancers when treated very early.

The very nature of cancer makes treatment difficult. Because the cells involved are difficult for the immune system to recognize as dangerous, the body is typically inefficient at destroying them. Many of the treatments, other than surgical removal, rely on the fact that cancer cells divide much faster and more frequently than normal cells. Therefore, any agent that can cause higher mortality in rapidly dividing cells has potential as a cancer treatment. Chemotherapeutic agents are essentially toxic chemicals that are most toxic to dividing cells. Thus, they kill cancer cells much more readily than most other body cells, but any other body cells undergoing cell division are susceptible, so chemotherapy also kills some normal cells. Cancer patients often feel very ill during chemotherapy because of this, although medication such as antinausea drugs can help to varying degrees.

Radiation therapy works similarly, being more damaging to dividing cells. An added advantage of radiation therapy, if the tumor has not yet metastasized, is that it can be focused more intensely in the vicinity of the tumor, preventing damage to other tissues. If the tumor has metastasized, then more widespread exposure to radiation may be used, with the obvious drawback that many other normal cells will also be damaged. Radiation therapy is often used to treat leukemia. Radiation is used to kill the patient’s bone marrow, and then new bone marrow is transplanted from a compatible donor. The new bone marrow can then restore normal function to the production of blood cells.

Genetics has played a part in improving chemotherapy. It has long been known that some people will respond better than others to certain chemotherapeutic drugs. It is now known that some of these differences are genetic, and the underlying genetic differences have been uncovered in some cases. Therefore, as part of cancer treatment for some kinds of cancer, a person may be tested genetically to make more intelligent choices about which drugs to use. Using this approach, doctors can prescribe patients targeted drugs that fight cancer in various specific ways, such as by blocking the signals telling cancer cells to grow and divide, preventing the formation of blood vessels that feed cancer cells, or triggering the immune system to kill cancer cells. As more genetic data become available, it is anticipated that more effective and personalized treatments will be developed.

Targeted Therapy

The Human Genome Project opened a new avenue of cancer therapy called targeted therapy. The availability of gene and protein databases led to the identification of hundreds of human proteins and kinases that may harbor mutations and play a role in cancer development. Monoclonal antibodies or small molecule kinase inhibitors are two therapies that act directly on these kinases. These products promise greater efficacy than blanket chemotherapy while keeping associated adverse effects to a minimum. Because kinase mutations tend to be found only in cancerous cells, normal healthy cells are largely unaffected by the targeted therapy. However, in most cases, before targeted therapy can be prescribed, additional testing of the tumor is required. If the tumor does not have one of the specific mutations that available targeted therapies attack, the treatment will not work because there is nothing to target. Another issue with targeted therapies is that cancers may become resistant to them through further mutations; as such, the National Cancer Institute recommends using them in combination with each other or with traditional chemotherapy drugs.

Targeted therapies that are available are directed against a variety of proteins and are effective for a number of types of cancer. Agents targeting the epidermal growth factor receptor (EGFR-type I) pathway, for example, disrupt the signals that mediate cell growth. Several EGFR agents have been approved by the Food and Drug Administration (FDA) for cancer treatment, such as cetuximab (Erbitux) and panitumumab (Vectibix) for colorectal cancer; cetuximab for head and neck cancer; cetuximab and erlotinib (Tarceva) for pancreatic cancer; trastuzumab (Herceptin) and lapatinib (Tykerb) for breast cancer; erlotinib for hepatocellular carcinoma; trastuzumab and ramucirumab (Cyramza) for esophageal and stomach cancers; and cetuximab, erlotinib, ramucirumab, and gefitinib for lung cancer.

Other targeted therapies block the activity of ABL, which is a protein that controls cell proliferation in chronic myeloid leukemia (CML). CML cells have a genetic mutation that results in partial sequences of the ABL and BCR genes merging with each other. The kinase inhibitor imatinib (Gleevec) targets these cells specifically, leading to complete remission in 75 percent of patients newly diagnosed with CML and 40 percent remission rates in patients with CML who have failed other therapies. Since almost all patients with CML have the BCR-ABL fusion gene, kinase inhibitors have the potential to work in most cases, and additional testing is usually not required for kinase inhibitors to be prescribed.

Another approach of targeted therapies is to inhibit angiogenesis. Bevacizumab (Avastin) is an antivascular endothelial growth factor (anti-VEGF) agent that prevents cancer cells from building a vascular network, depriving them of their nutrient base and essentially starving them. Bevacizumab is used for treating colorectal cancer, breast cancer, renal cell cancer, hepatocellular cancer, and pancreatic cancer. Pazopanib (Votrient) is used in the treatment of advanced renal cell carcinomas and soft tissue sarcomas.

Sunitinib (Sutent) and sorafenib (Nexavar) target multiple kinases to prevent tumor growth, angiogenesis, and metastasis. Sunitinib has been approved for the treatment of renal cell cancer, gastrointestinal stromal tumors, and pancreatic cancer; sorafenib is approved for treating hepatocellular cancer, renal cell cancer, and thyroid cancer.

Lastly, a class of targeted therapies called mTOR inhibitors inhibit a specific protein that disrupts the cascade signaling cell growth. Temsirolimus (Torisel) is used for treating renal cell cancer, and everolimus (Afinitor) is used in the treatment of some types of breast cancer, pancreatic cancer, gastrointestinal cancer, lung cancer, brain cancer, and renal cell carcinoma.

In addition to these, targeted therapies that are available include hormone therapies, gene expression modulators, signal transduction inhibitors, and apoptosis inducers. These therapies are not available for all cancers. Hormone therapy, for example, is only available for prostate and breast cancers.

Innovations and Future Treatments

Although the immune system cannot normally identify cancer cells accurately, there has been some success in immunological approaches. Research is progressing on the development of vaccines against cancer, but so far this approach is still in its early experimental stages.

Photodynamic therapy is another alternative treatment that has been successful in treating certain kinds of cancers. It is based on the observation that certain chemicals, when ingested by single-celled organisms, release damaging oxygen radicals when exposed to light, thus killing the organisms. It has been observed that cancer cells retain these chemicals longer than normal cells. Treatment involves administering the chemical by injection, then waiting for a specified period for it to be retained by cancer cells and flushed out of normal cells. Then the tissue in which the cancer cells are located is exposed to laser light. This method works on any tissues that can be exposed to laser light, which includes any part of the body accessible to endoscopy. While it is only effective on cancer cells that are contained and accessible to sunlight, photodynamic therapy can be more precise and less damaging than radiation and is less invasive than a surgical approach.

Information from the Human Genome Project is being used not only to develop new, more specific therapies but also to control adverse events and to identify which patients will benefit most from a particular therapy. Researchers are exploring whether genes that predict cancer risk may also predict outcomes and susceptibility to symptoms such as fatigue and depression. Furthermore, biomarkers are being examined as predictors of cancer risk and treatment effectiveness. Many clinical trials include genetic assessments in an attempt to find specific markers that identify those patients most likely to respond to a particular therapy. For example, researchers know that women with breast cancer who have an overproduction of the protein HER-2 are much more likely to respond to trastuzumab therapy.

The ultimate treatment for cancer would be replacement or repair of the mutated genes responsible. Currently, such treatment is not possible. There are many hurdles to overcome, including designing safe methods for inserting corrected gene copies. There is danger that improper gene therapy methods could actually make things worse, causing additional tumors or other diseases. A much better understanding of the genetics of cancer and future improvements in gene therapy techniques hold the promise of someday being able to cure or prevent most kinds of cancer.

Key Terms

• carcinogena substance or other environmental factor that produces or encourages cancer
• oncogenesgenes that cause cancer but that, in their normal form, called proto-oncogenes, are important in controlling the cell cycle and related processes
• tumora mass formed by the uncontrolled growth of cells, which may be malignant (considered cancerous) or benign (nonmalignant)
• tumor-suppressor genesgenes involved in regulating the cell cycle and preventing cell division until an appropriate time; when mutated, these genes can cause cancer

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