What Are Oncogenes and Proto-Oncogenes?
How Oncogenes and Tumor Suppressor Genes Can Lead to Cancer
Medically reviewed by Gagandeep Brar, MDFact checked by Angela Underwood
Humans have about 20,000 genes, which determine everything from hair and eye color, to blood type. Cancer is considered a genetic disease because it is caused by changes, or mutations, in genes that control the way cells grow and multiply.
A combination of mutations involving the following genes are frequently involved in cancer development:
Oncogenes are mutated forms of normal genes (called proto-oncogenes) that promote cell growth. Once mutated, oncogenes trigger "gain-of-function" activities, which may promote cancer development or make cancer more difficult to treat.
Tumor suppressor genes normally manage cell growth and prevent tumor development. Mutations in these genes trigger "loss of function," which may promote tumor development and growth.
DNA repair genes are genes that fix mistakes in DNA or trigger cells that cannot be fixed to die. Mutations in DNA repair genes lead to more mistakes within the cell, which can promote tumor growth.
This article takes a closer look at the role of oncogenes in cancer, along with how they differ from tumor suppressor genes and DNA repair genes. It also provides examples of oncogenes and the cancers they can cause.
What Are Oncogenes?
Proto-oncogenes are normal cellular genes that help cells grow, divide, and stay alive. Every person has them.
In most people, proto-oncogenes never mutate into oncogenes. If a mutation does occur, the gene can start to "turn on" in an uncontrolled manner, at which point it is called an oncogene.
Unlike proto-oncogenes, an oncogene will not turn off when it should. As a result, cells can grow out of control, potentially leading to the growth of a cancerous tumor.
Related: Cancer Cells vs. Normal Cells: How Are They Different?
Examples of Oncogenes
Oncogenes most frequently linked to cancer include:
MUC16: An oncogene that is mutated in about 19% of all tumors. It has been found in cancers of the pancreas, breast, lung, ovaries, and more.
PIK3CA: An oncogene that is mutated in about 12% of all tumors. It has been found in cancers of the breast, lung, stomach, ovary, brain, colon, rectum, and more.
KRAS: An oncogene that is mutated in about 11% of all tumors. It has been found in cancers of the lung, colon, rectum, pancreas, and more.
BRAF: An oncogene that is mutated in about 7% of all tumors. Around half of all melanomas have the BRAF mutation. It is also linked to leukemia, non-Hodgkin lymphoma, and cancers of the thyroid, ovaries, lungs, colon, rectum, and more.
Takeaway
Several gene mutations typically precede the development of cancer. Certain pairs of gene mutations are linked to a greater risk of certain cancers, too. For example, co-occurring BRAF and NRAS mutations have a particularly strong link to melanoma.
Related: Melanoma Facts and Statistics: What You Need to Know
What Causes Oncogenes to Activate?
Oncogenes may be activated due to inherited causes, or they can activate upon short or prolonged exposure to carcinogens (cancer-causing agents) in the environment.
Carcinogens
Environmental carcinogens both occur naturally and are generated by humans. Known carcinogens include:
Ultraviolet (UV) rays from the sun
Certain viruses, including human papillomavirus (HPV), hepatitis B virus (HBV), and Epstein-Barr virus (EBV)
Arsenic, often in contaminated plants or water
Aflatoxins, a fungi found on corn, peanuts, tree nuts, and other plants
Asbestos, a group of minerals found in construction and building materials, such as vinyl flooring and insulation, as well as contaminated rocks and soil
Formaldehyde, found in building insulation, household glues, paints, and lacquers, and preservatives used in some medicines, cosmetics, dishwashing liquids, and fabric softeners
Coal emissions
Engine exhaust and diesel
Ionizing radiation, found in natural sources like soil and vegetation, and manmade sources like x-ray machines
Outdoor air pollution
The consumption of processed meat
Welding fumes
Tobacco smoke is strongly associated with the development of various cancers. It contains over 7,000 chemicals that are breathed in both by the smoker and anyone exposed to secondhand smoke. At least 69 of those chemicals, including arsenic, benzene, cadmium, and formaldehyde, are carcinogens.
Takeaway
Exposure to a carcinogen can either trigger a proto-oncogene to mutate, or amplify a pre-existing mutation. KRAS mutations in lung cancer, for example, are more common in people who have smoked than never smokers.
Related: Foods That May Cause Cancer
Genetic Causes
Most mutations that activate oncogenes are not inherited, but rather acquired throughout a person's lifetime.
Nonetheless, DNA damage may occur as an accident during the normal growth of cells. So, even if we lived in a world free from carcinogens, cancer would occur.
Gene-related causes of oncogene activation include the following:
Gene variations in a person's genetic code can activate an oncogene. These variations may be inherited from a parent, or simply occur due to a mistake in the code that happens during otherwise normal cell division.
Epigenetic changes refer to chemical modifications in a genetic sequence that change the expression of the gene without permanently altering its code. These changes are reversible through lifestyle modifications, such as diet and exercise.
Chromosome rearrangements refers to a change in DNA sequencing that results in oncogene activation.
Gene duplication occurs when cells have extra copies of a gene. As a result, the cells may produce too many proteins. These proteins can increase signals that help cancer cells grow.
Family cancer syndromes: Only 5% to 10% of all cancers are linked to gene defects inherited from a parent. However, your chances of developing cancer may be higher if it runs in your family. Hereditary breast and ovarian cancer syndrome (HBOC) is one such syndrome linked to inherited BRAC1 or BRCA2 gene mutations.
Takeaway
It's important to note that oncogenes do not always cause cancer, nor does exposure to a carcinogen mean you will certainly develop cancer.
Related: An Overview of Lynch Syndrome
How Do Oncogenes Cause Cancer?
Oncogenes cause cancer through what's known as gain-of-function (GOF). In other words, the oncogene gains new functions or expresses itself in new ways as a result of the mutation.
Oncogenes can promote the following GOF activities:
Cell proliferation is the speed at which a cancer cell copies its DNA and divides into two cells. Oncogenes that promote cell proliferation are linked to more aggressive cancer.
Metastasis refers to the development of tumor growths that are distant from the primary cancer site. Oncogenes that promote metastasis are linked to more widespread cancer.
Genomic instability refers to the increased risk of DNA mutations occurring during cell division. Oncogenes that promote genomic instability are linked to a higher risk of cancer development, as cancer frequently develops from multiple gene mutations.
Metabolic reprogramming is the ability of cancer cells to adapt and become more resistant to changes in the "tumor environment." Oncogenes that promote metabolic reprogramming are linked to more invasive and metastatic cancer.
Cancer cell stemness refers to the ability of cancer cells to self-renew, differentiate into cells with new functions, and multiply. Oncogenes that promote cell stemness are linked to more metastatic and treatment-resistant cancers, as well as a greater risk of relapse.
Tumor microenvironment reshaping relates to a tumor's ability to reshape its environment in order to enhance its growth and increase its resistance against the immune system. Oncogenes that promote tumor microenvironment reshaping are linked to more aggressive, treatment-resistant cancers.
Immune suppression pertains to the tumor's ability to evade the immune system, making it more difficult for the immune system to detect and destroy cancer cells. Oncogenes that promote immune suppression are linked to more treatment-resistant cancers.
Resistance to cancer therapy refers to the cancer cells' ability to mutate and adapt to the tumor's environment in a way that makes it more resistant to anti-cancer drugs. Identifying which oncogenes are at play is important for selecting the right treatment.
Related: How Does Cancer Become Resistant to Chemotherapy?
What Are Tumor Suppressor Genes?
Whereas oncogenes cause cancer through gain-of-function activities, tumor suppressor genes cause cancer through loss of function.
Tumor suppressor genes help repair damaged DNA or eliminate damaged cells. These proteins can reduce the risk of cancer even when an oncogene is present.
Mutations in tumor suppressor genes cause them to lose this function. The likelihood of cancer developing thus increases, as abnormal cells cannot be repaired, and continue to survive instead of undergoing apoptosis (programmed cell death).
Tumor suppressor genes most frequently linked to cancer include:
TP53: A tumor suppressor gene that is mutated in about 37% of all tumors. TP53 is mutated in more than 90% of ovarian cancers and is implicated in an array of other cancers.
CSMD3: A tumor suppressor gene that is mutated in about 14% of all tumors. It is linked to melanoma and cancers of the ovaries, lungs, and more.
LRP1B: A tumor suppressor gene that is mutated in about 14% of all tumors. It is linked to melanoma and cancers of the lungs, stomach, and more.
There are several differences between oncogenes and tumor suppressor genes:
Oncogenes
Most often autosomal dominant, meaning that only one copy of the gene needs to be mutated to elevate cancer risk
Turned on by a mutation (a gain of function)
Can be visualized as the accelerator, when viewing a cell as a car
Tumor Suppressor Genes
Most often (but not always) autosomal recessive, a mutation in both copies must occur before it increases the risk of developing cancer
Turned off by a mutation (a loss of function)
Can be visualized as the brake pedal, when viewing the cell as a car
What Are DNA Repair Genes?
If oncogenes are the accelerator, and tumor suppressor genes are the brake pedal, then DNA repair genes can be thought of as the repair mechanic.
DNA repair genes are tasked with fixing mistakes in DNA. If they cannot fix the DNA, then the DNA repair genes trigger the cell to die so that harmful mutations cannot occur.
A mutation in a DNA repair gene causes loss of function. As a result, mistakes within cells may accumulate and lead to the development of cancer.
Just like oncogenes and tumor suppressor genes, mutations in DNA repair genes can be inherited at birth or acquired throughout a person's life.
Two of the most well-known DNA repair genes implicated in cancer are BRCA1 and BRCA2. About 3% of breast cancers and 10% of ovarian cancers result from inherited mutations in BRCA1 and BRCA2. These gene mutations also increase the risk of pancreatic cancer and high grade prostate cancer.
Related: BRCA Mutations and Breast Cancer
Oncogenes and Cancer Treatment
Research on oncogenes has played a significant role in some of the newer treatment options for cancer, as well as understanding why some particular treatments may not work as well for some people.
Cancers and Oncogene Addiction
Cancer cells tend to have many mutations that can affect a number of processes in the growth of the cell. Some of these oncogenes play a greater role in the growth and survival of cancer cells than others.
For example, several oncogenes are associated with breast cancer, but only a few seem to be essential for cancer to progress. When cancers rely on these particular oncogenes, it is known as oncogene addiction.
Researchers have taken advantage of this phenomenon by designing anti-cancer drugs that target the proteins produced by these "addicted" genes. These drugs are known as targeted therapies.
Examples of targeted therapies include:
Gleevec (imatinib): This medication is used to treat chronic myelogenous leukemia. It works by blocking the action of BCR-ABL, a protein that signals cancer cells to multiply.
HER2 monoclonal antibodies are drugs used to treat breast cancer. In about 10% to 20% of breast cancers, the cancer cells produce too much HER2, a protein that promotes cancer cell growth. HER2-targeted therapies work by attaching to this protein and telling it to stop cells from growing.
EGFR-targeted therapies are medications used to treat head and neck cancers, including lung cancer. The therapies work by blocking the actions of EGFR, a protein that promotes the growth and survival of cancer cells.
BRAF inhibitors are drugs used to treat melanomas with a BRAF oncogene addiction.
Other targeted therapies include:
The KRAS oncogene in pancreatic cancer
The cyclin D1 protein in esophageal cancer
The cyclin E protein in liver cancer
The beta-catenin protein in colon cancer
Related: Targeted Therapies for Breast Cancer
Oncogenes and Immunotherapy
An understanding of the proteins produced by oncogenes has also helped researchers begin to understand why some people with cancer may respond better to immunotherapy drugs than others. For example, people with lung cancer containing an EGFR mutation are less likely to respond to drugs called checkpoint inhibitors.
In 2004, one researcher found that cancer cells with RAS mutations also produced a cytokine (interleukin-8) that suppresses the immune response. A large percentage of pancreatic cancers have RAS mutations, and it's thought that the suppression of the immune response by the oncogene may help explain why immunotherapy drugs have been relatively ineffective in treating these cancers.
Other oncogenes that appear to negatively affect the immune system include EGFR, beta-catenin, MYC, PTEN, and BCR-ABL.
Takeaway
As further information becomes available, it's likely that these discoveries will not only lead to further therapies to treat cancer, but help unravel the processes by which cancer begins so that preventive actions can be taken.
Summary
Cancer is considered a genetic disease, as it is triggered by mutations in genes that cause cells to grow out of control. Usually, a combination of mutations in proto-oncogenes (which turn them into oncogenes), tumor suppressor genes, and DNA repair genes is involved.
Some mutations are associated with certain cancers. For example, most ovarian cancers are linked to a mutation in the TP53 tumor suppressor gene. The presence of a gene mutation does not always mean that you will get cancer, and you can reduce your risk of cancer by avoiding carcinogens, eating a healthy diet, and exercising.
Read the original article on Verywell Health.
