ONCOGENES AND TUMOR SUPPRESSOR GENES

ONCOGENES
A gene that is capable to produce cancer cells when activated. Oncogenes are generally mutated forms of normal cellular genes which are termed as proto-oncogenes. These alterations are usually somatic events, although germ-line mutations can affect a person to heritable cancer.

PROTO-ONCOGENES TO ONCOGENES TO CANCER

Proto-oncogenes are a group of genes that cause normal cells to become cancerous when they are mutated. Mutations in proto-oncogenes are typically dominant in nature, and the mutated version of a proto-oncogene is called an oncogene. Often, proto-oncogenes encode proteins that functions to stimulate cell division, inhibit cell differentiation, and stop cell death. All of these processes are important for normal human development and for the maintenance of tissues and organs. Oncogenes, however, typically show increased production of these proteins, thus leading to increased cell division, decreased cell differentiation, and inhibition of cell death; which ultimately leads to the production of cancer cells. Thus, oncogenes are currently a major molecular target for anti-cancer drug design.

Transformation events in cancer have been defined as initiation events or progression events.

HOW PROTO-ONCOGENES BECOME ONCOGENES

Today, more than 40 different human proto-oncogenes are known. But what types of mutations convert these proto-oncogenes into oncogenes ? Oncogenes are forms as a result of mutations that increase activity of a proto-oncogene. Fundamental genetic mechanisms associated with oncogene activation include the following:
• Point mutations, deletions, or insertions that lead to a hyperactive gene product
• Point mutations, deletions, or insertions in the promoter region of a proto-oncogene that lead to increased transcription
• Gene amplification events leading to extra chromosomal copies of a proto-oncogene
• Chromosomal translocation events that relocate a proto-oncogene to a new chromosomal site that leads to higher expression
• Chromosomal translocations that lead to a fusion between a proto-oncogene and a second gene, which produces a fusion protein with oncogenic activity

WHAT ARE MUTATIONS?

Mutations are the sudden inheritable change that takes place in the genes. Mutations are gene defects. Mutations involve changes in the arrangement of the bases that make up a gene. Even a change in just one base in the thousands of bases that make up a gene can have a major effect.
A mutation can affect the cell in many ways. Some mutations stop a protein from being made at all. Others may change the protein that is made so that it no longer works the way it should or it may not even work at all. Some mutations may cause a gene to be turned on, and make more of the protein than usual. Some mutations don't have a noticeable effect, but others may lead to a disease. For example, a certain mutation in the gene for hemoglobin causes the disease, sickle cell anemia.
They are usually of two types namely; Hereditary Mutations are gene defects that are passed from a parent to child. Some people are more likely to develop cancer than others simply because they are born with mutations in their genes. Other type is termed as Acquired Mutations. An acquired mutation can be caused by things in the environment such as exposure to radiation or toxins.

It is important to realize that mutations in our cells happen all the time. Usually, the cell detects the change and repairs it. If it can't be repaired, the cell will get a signal telling it to die in a process called apoptosis. But if the cell doesn't die and the mutation is not repaired, it may lead to a person developing cancer.

TUMOR SUPPRESSOR GENES

Genes in the body that can suppress or block the development of cancer and prevent tumour formation. Their protein product inhibits mitosis. A tumor suppressor gene directs the production of a protein that is part of the system that regulates cell division. The tumor suppressor protein plays a role in keeping cell division in check. When mutated, a tumor suppressor gene is unable to do its job, and as a result uncontrolled cell growth may occur. This may contribute to the development of a cancer.

Example 1: RB - the retinoblastoma gene

Retinoblastoma is a cancerous tumor of the retina. It occurs in two forms:
Familial retinoblastoma and Sporadic retinoblastoma

Familial retinoblastoma:
Multiple tumors in the retinas of both eyes occurring in the first weeks of formative years
Familial retinoblastoma occurs when a baby inherits from one of its parents a chromosome (number 13) that has its RB locus deleted or otherwise mutated. The normal Rb protein controls the cell cycle. It integrates the signals reaching the cell to determine whether it is safe for the cell to complete the passage from G1 of the cell cycle to mitosis.

A random mutation of the remaining RB locus in any retinal cells -- which are nondividing cells and should not enter the cell cycle -- completely eradicates the inhibition done by the Rb protein, and the affected cell grows into a tumor. So, in this form of the disease, a germline mutation plus a somatic mutation of the second allele leads to the disease.

Sporadic retinoblastoma:
A single tumor appears in one eye sometime in early childhood before the retina is fully developed and mitosis in it ceases.

In this disease, both inherited RB genes are normal but a single cell suffers s a somatic mutation (often a deletion) in both in order to develop into a tumor. But such cases are very rare .
In both forms of the disease, the patient's life can be saved if the tumor is detected soon enough and the affected eyes are removed.

HOW CAN ONCOGENES AND TUMOR SUPPRESSOR GENES BE USED TO TREAT CANCER?

The discovery and understanding of oncogenes and tumor suppressor genes has led to the development of new kinds of cancer therapies. The following are some examples of genes that are cancer treatment targets.

In some cases of breast cancer, the cells make an excess amount of a protein called HER2/neu. This protein promotes the growth of cancer cells. Cancers with too much of this protein did not respond as well to certain chemotherapy drugs (namely, cyclophosphamide, methotrexate, and fluorouracil), A drug was also designed to specifically attack cells with too much HER2/neu called Trastuzumab (Herceptin®) which sticks to the HER2/neu protein so that the growth of the cancer cells is slowed down. It has already been found to be useful in treating women whose breast cancer cells have abnormalities of this gene and/or its protein. Studies are currently being done to see if it will be useful in treating people with other cancers. Another drug that targets the HER2/neu protein, lapitinib (Tykerb®), is also available and others are being tested in clinical trials.

There are some cancers which returns back or persist even after treatment and at times it becomes hard to detect. For example, in chronic myeloid leukemia (CML), the cancer cells have a gene change that brings the oncogene ABL to a place on another chromosome called BCR. This creates a new gene called, BCR-ABL, that makes a type of protein called a tyrosine kinase. Drugs have been created that target the BCR-ABL protein, killing the leukemia cells. These drugs include imatinib (Gleevec®), dasatinib (Sprycel®), and others. They have led to remission of the leukemia in most patients treated in the early stages of their disease.

Most gastrointestinal stromal tumors are caused by activation of the oncogene called KIT. Others are caused by activation of PDGFRA, another oncogene. The drug imatanib (Gleevec®) targets both of these oncogenes, and is able to shrink these tumors and help patients live longer.

HURDLES IN USING TUMORS SUPPRESSOR GENES.

When tumor suppressor gene is used for treating cancer patients have several problems to overcome.
A major stumbling block lies in how to get new DNA into the cancer cells. Another problem is that most cancers have several mutations, so replacing one gene may not be enough to stop the cancer cells from growing and spreading.

Scientists have attempted to treat some cancers that have mutations in the p53 gene by inserting normal p53 genes into viruses and then trying to infect tumor cells with these viruses. Lab tests have shown that the treated viruses can get into the tumor cells and restore the normal p53 gene. These cells then grow more slowly than the other cancer cells. But the overall results were disappointing, and studies of this drug have been stopped.

About Author / Additional Info:
I Have done Biotech in my under graduation and it interests me still.