What are Oncogenes and Proto-Oncogenes?

Oncogenes are mutated genes that can contribute to the development of cancer. In their non-mutated state, everyone has genes which are referred to as proto-oncogenes. When proto-oncogenes are mutated or increased in numbers (amplification) due to DNA damage (such as exposure to carcinogens), the proteins produced by these genes can affect the growth, proliferation, and survival of the cell, and potentially result in the formation of a malignant tumor.

There are many checks and balances in place, and the development of cancer most often requires mutations or other genetic changes in both oncogenes and tumor suppressor genes (genes that produce proteins that either repair or eliminate damaged cells).

How Oncogenes Cause Cancer

Cancer arises most often when a series of mutations in proto-oncogenes (causing them to become oncogenes) and tumor suppressor genes results in a cell growing uncontrollably and unchecked. The development of cancer, however, is much easier to understand by looking at the different steps and lack of regulation that occurs over time.

Proto-Oncogenes and Oncogenes

Proto-oncogenes are normal genes present in everyone's DNA. These genes are "normal" in that they play an important role in normal cell growth and division, and are particularly vital for the growth and development of the fetus during pregnancy.

These genes function as a blueprint that codes for proteins that trigger cell growth. The problem arises when these genes are mutated or activated later in life (if they become oncogenes), where they may result in the formation of a cancerous tumor.

While the products (proteins) produced by proto-oncogenes are subject to the presence of growth factors and other signals to stimulate cell growth, the products of oncogenes may lead to cell growth even when these other signals are not present. As a result, the cells begin to outnumber normal surrounding cells and form a tumor.

Modes of Activation (How Proto-Oncogenes Become Oncogenes)

There are a number of ways in which normal proto-oncogenes can become activated (changed) so that they become oncogenes. The process can begin when carcinogens (cancer-causing agents) in the environment cause a mutation or amplification of a proto-oncogene.

Studies on animals have shown that chemical carcinogens can cause the mutations that convert ras proto-oncogenes to oncogenes.This finding is fitting, as KRAS mutations in lung cancer are more common in people who have smoked than never smokers.

That said, DNA damage may occur as an accident during the normal growth of cells; even if we lived in a world free from carcinogens, cancer would occur.

DNA damage can take one of several forms:

• Point mutations: Changes in a single base (nucleotide), as well as insertions or deletions in DNA can result in the substitution of a single amino acid in a protein that changes the function.
• Gene amplifications: Extra copies of the gene result in more of the gene product (proteins that lead to cell growth) being produced or "expressed."
• Translocations/rearrangements: Movement of a portion of DNA from one place to another can occur in a few ways. Sometimes a proto-oncogene is relocated to another site on a chromosome, and because of the location, there is a higher expression (larger amounts of the protein is produced). Other times, a proto-oncogene may become fused with another gene that makes the proto-oncogene (now an oncogene) more active.

Mutations may also occur in a regulatory or promoter region near the proto-oncogene.

Oncogenes Versus Tumor Suppressor Genes

There are two types of genes that when mutated or otherwise changed, can increase the risk that cancer will develop: oncogenes and tumor suppressor genes. A combination of changes in both of these genes is frequently involved in the development of cancer.

Even when DNA damage such as point mutations occur to convert a proto-oncogene to an oncogene, many of these cells are repaired. Another type of gene, tumor suppressor genes, code for proteins that function to repair damaged DNA or eliminate damaged cells.

These proteins can help reduce the risk of cancer even when an oncogene is present. If mutations in tumor suppressor genes are also present, the likelihood of cancer developing is greater as abnormal cells are not repaired and continue to survive instead of undergoing apoptosis (programmed cell death).

There are several differences between oncogenes and tumor suppressor genes:

From Mutations to Cancer

As noted earlier, cancer usually begins following an accumulation of mutations in a cell including those in several proto-oncogenes and several tumor suppressor genes. At one time it was thought that activation of oncogenes resulting in out-of-control growth was all that was necessary to transform a normal cell to a cancer cell, but we now know that other changes are most often needed as well (such as changes that prolong survival of deranged cells).

These changes not only lead to cells that grow and divide uncontrollably, but that also fail to respond to normal signals for cells to die, fail to respect boundaries with other cells (lose contact inhibition), and other characteristics that cause cancer cells to behave differently than normal cells.

A few types of cancer, however, are associated with only single-gene mutations, with an example being childhood retinoblastoma caused by a mutation in a gene known as RB1.

Heredity (Germline) Versus Acquired (Somatic) Mutations

Talking about mutations and cancer can be confusing because there are two different types of mutations to consider.

• Germline mutations: Hereditary or germline mutations are gene mutations that are present at birth and exist in all of the cells of the body. Examples of germline mutations are those in the BRCA genes (tumor suppressor genes) and non-BRCA genes that increase the risk of developing breast cancer.
• Somatic Mutations: Somatic or acquired mutations, in contrast, are those that occur after birth and are not passed down from one generation to another (not hereditary). These mutations are not present in all cells, but rather occur in a particular type of cell in the process of that cell becoming malignant or cancerous. Many of the targeted therapies used to treat cancer are designed to address changes in cell growth caused by these particular mutations.

Oncoproteins

Oncoproteins are the product (the proteins) that are coded for by oncogenes and are produced when the gene is transcribed and translated (the process of "writing down the code" on RNA and manufacturing the proteins).

There are many types of oncoproteins depending on the specific oncogene present, but most work to stimulate cell growth and division, inhibit cell death (apoptosis), or inhibit cellular differentiation (the process by which cells become unique). These proteins can also play a role in the progression and aggressiveness of a tumor that is already present.

History

The concept of oncogenes had been theorized for over a century, but the first oncogene was not isolated until 1970 when an oncogene was discovered in a cancer-causing virus called the rous sarcoma virus (a chicken retrovirus). It was well known that some viruses, and other microorganisms, can cause cancer and in fact, 20% cancers worldwide are caused by these invisible organisms.

The majority of cancers, however, do not arise in relation to an infectious organism, and in 1976 many cellular oncogenes were found to be mutated proto-oncogenes; genes normally present in humans.

Since that time much has been learned about how these genes (or the proteins they code for) function, with some of the exciting advances in cancer treatment derived from targeting the oncoproteins responsible for cancer growth.

Types and Examples

Different types of oncogenes have different effects on growth (mechanisms of action), and to understand these it's helpful to look at what is involved in normal cell proliferation (the normal growth and division of cells).

Most oncogenes regulate the proliferation of cells, but some inhibit differentiation (the process of cells becoming unique types of cells) or promote survival of cells (inhibit programmed death or apoptosis). Recent research also suggests that proteins produced by some oncogenes work to suppress the immune system, reducing the chance that abnormal cells will be recognized and eliminated by immune cells such as T-cells.

While there are more than 100 different functions of oncogenes, they can be broken down into several major types that transform a normal cell to a self-sufficient cancer cell. It's important to note that several oncogenes produce proteins that function in more than one of these areas.

Growth Factors

Some cells with oncogenes become self-sufficient by making (synthesizing) the growth factors to which they respond. The increase in growth factors alone doesn't lead to cancer but can cause rapid growth of cells that raises the chance of mutations.

An example includes the proto-oncogene SIS, that when mutated results in the overproduction of platelet-derived growth factor (PDGF). Increased PDGF is present in many cancers, particularly bone cancer (osteosarcoma) and one type of brain tumor.

Growth Factor Receptors

Oncogenes may activate or increase growth factor receptors on the surface of cells (to which growth factors bind).

One example includes the HER2 oncogene that results in a significantly increased number of HER2 proteins on the surface of breast cancer cells. In roughly 25% of breast cancers, HER2 receptors are found in numbers 40 times to 100 times higher than in normal breast cells. Another example is the epidermal growth factor receptor (EGFR), found in around 15% of non-small cell lung cancers.

Signal Transduction Proteins

Other oncogenes affect proteins involved in transmitting signals from the receptor of the cell to the nucleus.

Non-Receptor Protein Kinases

Non-receptor protein kinases are also included in the cascade that carries the signal to grow from the receptor to the nucleus.

A well-known oncogene involved in chronic myelogenous leukemia is the Bcr-Abl gene (the Philadelphia chromosome) caused by a translocation of segments of chromosome 9 and chromosome 22. When the protein produced by this gene, a tyrosine kinase, is continually produced it results in a continuous signal for the cell to grow and divide.

Transcription Factors

Transcription factors are proteins that regulate when cells enter, and how they progress through the cell cycle.

An example is the Myc gene that is overly active in cancers such as some leukemias and lymphomas.

Cell Cycle Control Proteins

Cell cycle control proteins are products of oncogenes that can affect the cell cycle in a number of different ways.

Some, such as cyclin D1 and cyclin E1 work to progress through specific stages of the cell cycle, such as the G1/S checkpoint.

Regulators of Apoptosis

Oncogenes may also produce oncoproteins that reduce apoptosis (programmed cell death) and lead to prolonged survival of the cells.

An example is Bcl-2, an oncogene that produces a protein associated with the cell membrane that prevents cell death (apoptosis).

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, but some of these oncogenes (mutated or damaged proto-oncogenes) play a greater role in the growth and survival of cancer cells than others. For example, there are several oncogenes that are associated with breast cancer, but only a few that seem to be essential for cancer to progress. The reliance of cancers on these particular oncogenes is referred to as oncogene addiction.

Researchers have taken advantage of this reliance on particular oncogenes—the proverbial "Achilles heel" of cancer—to design drugs that target the proteins produced by these genes. Examples include:

• The medication Gleevec (imatinib) for chronic myelogenous leukemia that targets the signal transducer abl
• HER2 targeted therapies that target cells with a HER-2/neu oncogene addiction in breast cancer
• EGFR targeted therapies for cancers with an EGFR oncogene addiction in lung cancer
• BRAF inhibitors in melanomas with a BRAF oncogene addiction
• Drugs such as Vitrakvi (larotrectinib) that inhibit proteins produced by NTRK fusion genes and can be effective a number of different cancers containing the oncogene
• Other targeted therapies including medications that target Kras in pancreatic cancer, cyclin D1 in esophageal cancer, cyclin E in liver cancer, beta-catenin in colon cancer, and more

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, why people with lung cancer containing an EGFR mutation are less likely to respond to checkpoint inhibitors.

In 2004, one researcher found that cancer cells with RAS mutations also produced a cytokine (interleukin-8) that works to suppress 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.

A Word From Verywell

An understanding of proto-oncogenes, oncogenes, and tumor suppressor genes is helping researchers understand both the processes that result in the formation and progression of cancer and methods of treating cancers based on the particular effects of the products of oncogenes. 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 as well.