CANCER RESEARCH

Gene Mutation

Gene mutation

The topics on this page are:

  • Gene mutations and cancer
  • Genetic mutations and cancer
  • Type of genetic mutation
    • Point mutation
    • Translocation
    • Gene amplification
    • Reverse, delete, repeat
    • Aneuploidy
    • Genetic change
  • Cause of gene mutation
  • Summary of gene mutations
  • Understanding the process: genetic mutation

 

Cancer is formed by the failure of the function of the control cells. The cause of functional failure is always related to changes in important genes. These changes are often caused by genetic mutations , or changes in the DNA sequence of the chromosome . A genetic mutation may be a small change that affects only a few nucleotides, or a large change that affects a major change in the structure of a chromosome.

Both small and large mutations can affect cell behavior. Multiple mutations in important genes can cause cancer. The content of this chapter describes the association of variation and cancer, the different types of variation and their causes.

Genetic variation and cancer

The abnormal behavior exhibited by malignant tumors is caused by a series of mutations in important genes. As more genes are damaged, cells become more and more abnormal. It is often the case that the genes that control DNA repair are themselves damaged, making cells more sensitive to increasingly severe genetic damage.

Below is an animation showing the relationship between chromosomes, genes and DNA.

Most malignant tumors are thought to be precursor cells that originate from a single mutation. When such precursor cells divide, the formed “child” cells will undergo different mutations and behaviors after a period of time. Those cells that have gained the opportunity for cell division or have overcome cell death will most likely “take over” the entire cell population and play a dominant role. In this way, cancer cells acquire the ability that various normal healthy cells do not have. The behavioral changes of cancer cells are the focus of this section of the Cancer Biology section of this website.

Mutations in important regulatory genes (tumor suppressor genes and proto-oncogenes) alter the behavior of cells and may lead to uncontrolled growth that is visible in malignant tumors.

For all types of cancers studied to date, the transformation of normal healthy cells into cancer cells appears to be a step-by-step process and requires many genetic changes to accumulate cancer cells. This genetic alteration occurs in oncogenes and also in tumor suppressor genes. This explains why malignant tumors are much more common among older people. To form malignant cells, a series of mutations must occur within the same cell. Since the probability of mutation in any gene is small, there is every reason to believe that the possibility of several different mutations occurring in the same cell is really small. Therefore, cells in the 70-year-old elderly have more time to accumulate the mutations necessary for cancer, and the cells in the child’s body are much less likely to acquire the necessary genetic changes. Of course, there are also children with malignant tumors, but older people are much more likely to develop cancer. The figure below shows the relationship between the incidence of colon cancer in the United States and age. This figure is provided by the National Cancer Institute.

Colon cancer as a function of age
The above curve changes can lead to the conclusion that the transformation of normal cells into cancerous cells requires multiple genetic changes .

In the laboratory, researchers have been trying to induce tumorigenesis by altering or introducing key regulatory proteins. Several studies have attempted to determine the minimum number of genetic mutations required to cause cancer cells to appear, and the results are interesting.

In nature, genetic mutations accumulate in cells, and variations in the “key” genome can lead to cancer. A study found in 2012 that bone marrow stem cells in healthy people may accumulate many variations during their growth. As long as the key genes are mutated several times, it can lead to cancer. This result shows that in many cases, “normal” nuclear cancer cells are not very different. 2

Genetic mutation in cancer

Obviously, the mutations needed for cancer formation can be caused in many different ways, which makes the problem more complicated. Although all cancers grow and develop through a series of identical control levels, the genes involved may vary . In addition, the order in which genes are out of control or lost may also differ. Even if two different patients have the same type of cancer (eg colon cancer), the tumor suppressor genes and oncogenes involved may be quite different.

The high degree of “heterogeneity” in the tumor (even in the same organ) makes diagnosis and treatment very complicated. At present, based on the progress of the molecular classification of tumors, we are able to develop a rational treatment plan based on the genes actually involved in the case. New diagnostic tests can screen hundreds or thousands of genes to create personalized files for patients. Such information allows cancer patients to obtain highly targeted treatments. For more information, see the genomic/proteomics section.

Gene mutations that cause uncontrolled cell growth can be caused in two different ways. After several years of genetic mutation can gradually form, causes cancer “sporadic”; the mutation may also be obtained by genetic, hereditary abnormal function of the gene can lead to hereditary cancer. Known cancers with hereditary factors are:

  • Breast Cancer – Genetically altered BRCA1 and BRCA2 genes are known risk factors for breast cancer. Although many, if not most, breast cancer patients do not detect mutations in these two genes, having such mutations increases the likelihood of breast cancer.
  • Defects in colon cancer -DNA repair genes (such as MSH2) make patients more susceptible to hereditary nonpolyposis colorectal cancer ( HNPCC ).
  • Eye cancer – Rb tumor suppressor genes ( tumor Suppressor defect) can cause eye cancer and several other types of cancer. For more on the disease, see the Rb chapter.

The types of hereditary cancers listed here are incomplete and, to be certain, more genetic cancers will be identified as research progresses in cancer genes.

More on this topic can be found in the second and fourth chapters of The Biology of Cancer by Robert A. Weinberg.

Type of genetic mutation

The synthesis process of proteins (ie, translation ) is based on the “interpretation” function of mRNA . The mRNA is “read” function through transcription ( Transcription ) process is obtained. Changes in the DNA encoded by the gene result in changes in the mRNA. Altered mRNA may lead to the formation of dysfunctional proteins. Even a single nucleotide (the DNA strand nucleotide changes) may result in complete loss of protein function.

DNA can be altered in several ways. The following pages detail different types of genetic changes.

Point mutation

Genetic variation is divided into two categories. The first type is the mutation of only one or a few nucleotides in the DNA strand. Such mutations are called point mutations .

When a ribosome “interprets” a messenger RNA molecule, every three nucleotides are translated into an amino acid. Such a three-digit “password” is called a codon. Take the English sentence as an analogy: “The fat cat ate the rat” This sentence contains 6 codons. The mutation causes a change like this: “The fat b at ate the rat.” or “The fa’ or The fat o ca tat her at…” The effect on the protein depends on the location and type of genetic variation.

The three codons interpreted by ribosomes may be altered by gene mutations in one of three ways:

Nonsense mutation

The new codon allows the protein to be stopped in advance, and the resulting protein is shortened and often non-functional.

 

Stop codon mutation
 

 

Missense mutation

The new codon inserts the wrong amino acid into the protein. The effect on the function of the protein is determined by what amino acid replaces the normal amino acid at the insertion position.

 

Amino acid mutation
 

 

Frameshift mutation

Loss or addition of one or two nucleotides causes the affected codon to be misinterpreted, and all codons are misinterpreted. The resulting proteins vary widely and are often non-functional.

 

Misread mutation
 

Transcription error

DNA damage can result in a single or a small set of nucleotide changes that cannot be “interpreted” by RNA polymerase. When RNA polymerase complexes reach these positions, they sometimes add nucleotides to continue to move around to “pass” these DNA damage, even if they add the wrong nucleotides. This process is called transcriptional mutation and plays an important role in the development of cancer. 3

Translocation

The second type of genetic mutation involves a relatively large amount of DNA mutations, and is often at the level of the chromosome . These changes are called translocations and involve the fragmentation and movement of chromosome fragments. It is often the case that a break in two different chromosomes is accompanied by a recombination of the genes, resulting in the formation of two “new” chromosomes.

It may seem that translocation does not pose a big problem because all genes still exist; in fact, these changes can lead to uncontrolled cell growth in a variety of ways –

1. These genes may not be properly transcribed and translated in new locations.
2. The movement of genes results in an increase or decrease in the degree of transcription.
3. Fragmentation and recombination can also occur within the gene (shown in green above), resulting in gene inactivation.

Special translocations are common in some cancers and can be used to diagnose these cancers. Translocations are common in leukemias and lymphomas, but less common in solid malignancies. For example, the exchange of chromosomes 9 and 22 can be seen in more than 90% of patients with chronic myelogenous leukemia. Chromosome exchange led to the shortening of chromosome 22, and the shortened 22 was called the “Philadelphia chromosome” (named after the place where it was found). Such translocation results in the production of the proto-oncogene abl .

Other cancers that are often (or always) associated with translocations include Burkitt’s lymphoma , B-cell lymphomas, and several leukemias.

Gene amplification

In the abnormal gene amplification process, the normal DNA replication ( Replication ) Process serious “holes.” As a result, it is not a copy but a copy of a copy from a certain region of the chromosome. This has led to a number of gene copies in this region. Sometimes, the replicated regions have so much yield, so that they actually form their own small pseudochromosomes, also called double microchromosomes.

 

Gene overproduction
 

 

Each gene on this copy can be transcribed and translated, results in amplification of the gene corresponding to the mRNA and protein ( Protein excessive synthesis), as follows. The curve in the figure indicates the mRNA formed by transcription of the gene.

 

 

This process is not present in normal cells, but is common in cancer cells. If the oncogene is located in the amplified region, overexpression of the gene can lead to uncontrolled cell growth. For example, amplification of myc oncogenes in many tumors , and amplification of ErbB-2 or HER-2/neu oncogenes in breast and ovarian cancers. The clinical treatment of the HER-2/neu oncogene is primarily directed to cells that overexpress protein products.

Overexpression of genes can also pose another major problem in cancer treatment: drug resistance. Drug-resistant tumors continue to grow and spread in the presence of chemotherapeutic drugs. A gene that is commonly involved is called MRD ( m ultiple d rug r esistance multidrug resistance). The product of this gene is the pump protein (transport protein) on the cell membrane. It selectively excretes molecules from cells, including chemotherapy drugs. This removal causes the drug to lose its effect.

These will be covered in more detail in the “Resistance” chapter. Amplification of different genes can invalidate different chemotherapy drugs.

Inversion, repetition, deletion, aneuploidy

Inversion

In such a change, the DNA segment is released from the chromosome and then reinserted in the opposite direction. As described in the above examples, this rearrangement causes abnormal expression of the gene by activating the oncogene or inactivating the tumor suppressor.

Repeat/miss

A gene or group of genes can be replicated more than once in a chromosome due to replication errors. This is different from gene amplification ( Gene Amplification), because the copy of this gene does not exceed the chromosome and is copied only once, not hundreds of times. These genes may be lost due to failure of the replication process or other genetic damage.

Extra chromosome copy

Aneuploidy

Aneuploidy is a genetic alteration associated with loss or increase of the entire chromosome. Due to problems in cell division, the replicated chromosomes are not accurately separated into two daughter cells. This leads to too many or too few chromosomes. Aneuploidy in Down’s syndrome (which is not associated with malignancy) is a common example, with a copy of chromosome 21 in all cells of the patient.

In the animation below, the chromosome is copied into two copies, but when the cell divides, the chromosome is not evenly divided into two newly formed cells (child cells). As a result, one cell has too many chromosomes and the other does not have enough chromosomes.

Aneuploidy is very common in cancer . Normal human cells have 46 chromosomes, but malignant cells have many more chromosomes, sometimes more than 100. The presence of too many chromosomes makes cells unstable, seriously affecting the control of cell division. Whether or not all cancer cells are aneuploid is currently controversial. Whatever the outcome, one thing is clear: aneuploidy is a common feature of cancer cells.

Epigenetic change

In addition to changes in DNA sequences, gene expression can also be altered by another change in DNA and chromatin, and this type of change does not alter the DNA sequence. Since this change does not affect the DNA sequence in a gene, so called exhibit genetic variation ( EPI Genetic Changes) . There are two types of manifested genetic changes.

Methylation

In this variation, some of the nucleotides in the DNA are altered by the addition of a methyl group (-CH3) to the base. Such DNA methylation is accompanied by inactivation of a certain region of DNA . Abnormal DNA methylation has been found in cancer cells. As described above, methylation alters the expression of the affected gene.

acylated

In this type of manifestation of hereditary changes, histones surrounding the DNA helix are altered by the addition of acetyl (-CH3CHO). Such changes result in attenuated interactions between DNA and histones, accompanied by an increase in gene expression . The changes caused by the addition of acetyl groups to DNA or the removal of acetyl groups from DNA are currently a hot topic in cancer treatment research.

For more information, see Performance Hereditary Changes and Cancer Treatment.

Cause of mutation

As we already know, malignant cells evolved from normal precursor cells, and this evolution is due to the accumulation of genetic damage. There are many mechanisms that lead to this change. Generally speaking, the way of gene mutation is roughly divided into three categories, which we will introduce in detail.

Spontaneous mutation

Spontaneous mutation : DNA bases may be because they are not in the repair of replication errors(replication error) or molecular contingency (random molecular events) changed or lost. For example, loss of amino groups in cytosine (normal bases in DNA) can result in uracil formation (bases that are not found in normal DNA). If this change is not detected and corrected, it can lead to mutations. Occasionally, the entire base may be lost due to a break in the bond between the DNA backbone and the base. This results in a gap in the DNA double helix; if not repaired, it can lead to mutations during the next DNA replication process.

Induced mutation

Induced mutations: Mutations may be induced by multiple events in the body (or cells). Some common induced mutations are:

Radiation – this is one of the first known mutations (mutagens). Radiation ( Radiation ) is a very strong mutagenesis thereof. Different types of radiation induce different types of genetic mutations. Ultraviolet (UV) induced point mutations. X-rays induce DNA double helix breaks and cause translocations, inversions and other types of chromosomal damage. Contact with ultraviolet light in the sun is associated with the development of skin cancer. It is worth noting that the property of radiation-induced DNA damage has been used in several different radiation-based cancer treatments.

Shown below is a mutation caused by ultraviolet radiation. In this example, the “bombardment” of ultraviolet light on the DNA double helix causes two bases to be linked together. This changes the structure of the DNA and can cause permanent changes if not repaired.

The release of energy from radioactive elements such as helium and uranium or from artificial sources in nuclear reactors brings another type of radiation. This type of radiation has different types and can cause damage to different types of cells and tissues. Radiation can directly damage DNA, or it can lead to the formation of chemical components (ie, reactive oxygen species) that can damage DNA or other cellular components.

Historically, radioactive materials and radiation have been well documented. An analysis of survivors of atomic bombing during the Second World War in Japan showed that the incidence of leukemia increased significantly shortly after exposure to nuclear radiation, and other types of cancer increased in the next few decades.

Nuclear power plants may also accidentally release a large amount of dangerous radioactive materials. Accidental nuclear leaks at the Chernobyl nuclear reactor are thought to be associated with an increase in the incidence of thyroid cancer and other cancers.

Medical imaging equipment (such as X-rays and CT scans) can also cause radiation to the patient. Radiation received during a single test does not cause a large number of cancer cases, but the impact of long-term multiple tests is unclear.  Similarly, a full-body scan of an aircraft passenger at an airport will not cause cancer.  Aircraft passengers are also exposed to radiation from space during flight 0, but this slight radiation does not increase the risk of cancer. Even the flight attendants will not be affected.

Chemical Mutants : We have learned that many different chemicals can cause mutations. The mechanism is that they bind to DNA or bind to certain components of DNA, interfering with normal replication or transcription. For example, both benzopyrene and aflatoxin are sources of strong mutations. Benzopyrene is a chemical in cigarette smoke; aflatoxin is most commonly found in improperly stored agricultural products.

Chronic inflammation : chronic inflammation (chronic  inflammation ) can lead to DNA damage, which is a chemical produced by the immune system cells due to mutations source. For example, hepatitis viruses can cause chronic inflammation. Learn more about viruses and cancer.

Oxygen free radicals : in the process of obtaining energy from the food (mitochondria occurs inmitochondria within), may have some chemical substances. These chemicals are very active and can damage cell membranes and DNA. Such reactive oxygen species (ROI:  r eactive o xygen i ntermediates) can be produced by irradiation of cells, as shown below.

The mutagenic activity of reactive oxygen species is associated with the development of cancer, and consensus is also associated with anticancer therapies (including radiation therapy and chemotherapy).

Abnormal cell division

During mitosis , cells may not be able to accurately distribute the replicated chromosomes into the two daughter cells during the division process. This type of error can lead to aneuploidy self-exposure. This cell is lost or extra genes are obtained. This rare process may create more cells with uncontrolled cell division. As mentioned above, most cancers in humans are polyploid.

If a cell’s mutant gene happens to “control” the cell division process, then the situation will quickly get out of control, and the daughter cells produced by each division will become more abnormal.

Virus and mutation

The virus is thought to be involved in the formation of many cancers. Viruses can cause cancer in a variety of ways, and each virus works in a slightly different way. Some viruses, including retroviruses, can cause mutations by inserting their own genes into the genome of infected cells. The inserted DNA can damage or alter the activity of the affected gene.

Viruses can directly cause genetic mutations. For example, hepatitis virus infection may last for many years. During this time, the body’s defense system may drive the virus by producing toxic chemical molecules. These chemical molecules can damage the otherwise healthy “bystander” cells and put them on the path of cancer. The virus has many ways to cause cancer.

Because of the importance of the virus in the formation of cancer, we have established chapters devoted to viruses and cancer.

Transposon and mutation

A transposon is a very short DNA sequence that can be transferred from one location on the DNA to another. The transposon is encoded by a transposase, and the transposase can splicing the transposon to a new location on the genome (the lower left panel shows a transposon). The transposon was discovered by Barbara McClintock, who won the Nobel Prize. The human genome contains a lot of missing or transposon copies, and these transposons lose their ability to move or “jump” to a new location. About 50% of human genes contain “inactivated” transposons.

The movement of active transposons may lead to genetic mutations by altering the activity of genes. A clear example of the activity of the transposon (inversion) is the color of the Indian corn granules (see figure below right). Active transposons in the human body are thought to be involved in human diseases, including cancer.

Schematic of a bacterial composite transposonIndian corn

Summary of gene mutations

Introduction to genetic changes (mutations)

  • Abnormal expression of cancer cells is caused by a series of mutations in key regulatory genes (ie, DNA repair genes).
  • Most cancers are thought to have evolved from single cells that have accumulated enough genetic variation to form cancer cells.

DNA mutation

  • Genetic changes may be small: affect only a single or a few nucleotides (point mutations), or large: alter the structure of one or several chromosomes
  • Point mutation
    • Translation is the process by which an enzyme synthesizes a protein by “reading” a “character” (codon) consisting of three nucleotides along the messenger RNA (mRNA).
    • Even changing only one nucleotide of the gene’s DNA strand completely disables the protein. Gene mutations are classified according to their effects on gene protein products:
      • Nonsense mutations – new (mutated) codons cause protein synthesis to stop prematurely.
      • Missense mutations  – altered codons result in incorrect amino acid insertion into the protein.
      • Frameshift Mutation  – Loss or increase of one or two nucleotides in an mRNA results in a misinterpretation of the codon. Often results in shortened or non-functional proteins.
  • Chromosome level changes
    • Translocation  – the cleavage of chromosome fragments and the exchange of (sometimes) fragments.
    • Gene amplification  – Abnormal replication forms multiple copies of a region on a chromosome. Ultimately this leads to overproduction of the corresponding gene.
    • Inversion – The DNA fragment is released from a chromosome and reinserted in the opposite direction.
    • Repeat/Deletion  – A gene or group of genes may be lost together or replicated multiple times on a single chromosome.
    • Aneuploidy  – Loss or gain of genetic changes throughout the chromosome.
  • Spontaneous variation may be caused by unrepaired DNA or random molecular events.
  • Aneuploidy is very common in cancer cells.

Hereditary changes

  • Gene expression may vary due to changes in DNA and chromosomes that do not alter the sequence of the gene. Such as DNA methylation and histone acetylation.
  • Methylation – Some nucleotides in DNA change due to the addition of methyl groups. Such DNA methylation is accompanied by inactivation of a certain region of DNA .
  • The addition of acetylation-acetyl groups loosens the DNA strand and enhances gene expression.

Induced mutation

  • Exposure of organisms (or cells) to the following treatments may result in mutations:
    • Radiation – Ultraviolet light causes point mutations, and X-rays cause multiple injuries.
    • Chemical mutagens – can bind to DNA components of DNA and interfere with replication or transcription processes.
    • Chronic inflammation – a mutagenic substance produced by the cells of the immune system that causes DNA damage.
    • Oxygen free radicals – produced during the energy production of cells and can damage DNA.

Other genetic changes

  • Abnormal cell division leads to division of incorrect chromosomes and produces aneuploidy.
  • Viruses can cause genetic damage in a number of ways, which is associated with many cancers.

Gene mutations and cancer

  • Changing from a normal, healthy cell to a cancer cell is a gradual process.
  • The development of cancer requires genetic changes in a number of different oncogenes and cancer suppressor genes.
  • For growth and development, all cancers must overcome a series of identical regulatory functions, but the genes involved may vary.
  • The heterogeneity of cancer makes diagnosis and treatment difficult.
  • A family-specific hereditary cancer may be caused by a genetically dysfunctional gene.

Understanding the process: genetic mutation

“Understanding the Process” is an interactive educational game that tests your knowledge. Start the game:

  • Select the appropriate options from the right column and drag them into the corresponding boxes on the left. Please note that you will only use five of the six options to complete the game.
  • When you’re done, click “Query” to see your correct rate.
  • For incorrect answers, click on “Description” to review the information.
  • If you want to try again, please select “Reset” and start the game again.

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