Mutagenesis and cancer

DEFINITION: Mutagenesis is the generation of changes or mutations in a cell's genetic material. Normally, the cells in the body maintain a critical balance between cell growth and proliferation and cell death. This balance is maintained by the action of several cellular mechanisms. When mutations occur that affect the cell's ability to maintain this balance, it can begin to proliferate uncontrollably, leading to tumor formation and, ultimately, cancer. Mutations can be inherited or acquired. Additionally, certain types of cancer cells show a characteristic increased rate of mutation, known as a mutator phenotype.

Mutagenesis and cancer formation: In normal cells, muliple redundant mechanisms tightly control cell proliferation and cell death processes. Therefore, multiple mutations are required to transform a normal cell into a cancer cell. Although the specific genes mutated in different tumors are highly variable, there is a common theme of the types of mutations that promote tumor formation. In general, mutations are likely to occur in two types of genesproto-oncogenes and tumor-suppressor genes.

A proto-oncogene is a gene that promotes cell growth, differentiation, and proliferation. When a proto-oncogene undergoes a mutation that promotes tumor-cell formation, it is known as an oncogene. Oncogenic mutations are dominant, which means that mutation of a single copy of the gene is sufficient to confer an increased risk of tumor formation. Conversion from a proto-oncogene into an oncogene can occur by several different mechanisms, most of which ultimately lead to increased levels of activity of the encoded protein. For example, mutations within the gene’s coding sequence can change the protein’s structure to increase its activity or disrupt its ability to be properly regulated. Mutations outside of the gene’s coding region can affect the expression of the protein, leading to increased levels within the cell.

The first identified oncogene, the tyrosine-protein kinase Src (c-Src), was discovered in 1970 from a chicken retrovirus. In normal, nontumor cells, c-Src is an enzyme that acts within several signaling pathways to promote cell proliferation, cell survival, protein translation initiation, metabolism, cell adhesion, and motility. The oncogenic form of the protein, v-Src, contains a mutation that abolishes a regulatory site on the protein, leading to its constitutive activation. Cells that contain the oncogenic form of Src can grow without cell proliferation signals and without being anchored down. These properties give transformed cells a selective growth advantage over normal, nontransformed cells, which can ultimately lead to uncontrolled growth and tumor formation.

The other common type of mutation found in cancer cells occurs within tumor-suppressor genes. In normal cells, tumor-suppressor genes help negatively regulate cell growth and proliferation. These genes produce proteins that prevent cells from dividing if there is deoxyribonucleic acid (DNA) damage or if the cell-division apparatus is compromised and without growth signals. Mutations in tumor-suppressor genes are characterized as recessive since both copies of the gene must be mutated. One of the most common mutations found in human cancers is within the tumor-suppressor gene TP53. When a cell experiences damage or stress, TP53 typically suppresses cell growth and proliferation and if the damage is severe enough, promotes cell death. Mutation of both copies of the TP53 gene allows cells to survive and proliferate even in the presence of DNA damage.

Multiple mutations in proto-oncogenes and tumor-suppressor genes are required to transform a normal cell into a cancer cell. This idea was made famous in 1971 by Alfred Knudson, who showed that the incidence of tumor formation was consistent with two mutational “hits.” For example, mutation of TP53 alone is insufficient to induce tumor formation since this mutation only effectively disengages the suppression of cell growth. This mutation does, however, confer on the cell a selective advantage, which usually causes it to produce more daughter cells than its neighbors that do not contain the mutation. Over time, the progeny of this original mutant cell may accumulate an oncogenic mutation that will allow it to grow and proliferate even more, potentially forming a tumor. Additional mutations can then occur that allow the cells to better survive in the harsh tumor environment, which contains very low levels of oxygen and nutrients, and metastasize into other body regions.

Inherited mutations: One way to acquire a mutation is to inherit it from a parent. Each cell in a person's body contains two copies of each gene, one inherited from each parent. Inheriting a mutated copy of a gene, such as a tumor suppressor, from one parent can strongly predispose a person to developing cancer. Normally, a cell must undergo mutation of both copies of a tumor-suppressor gene to abolish its function. However, if a person inherits a mutation in one copy of the gene, it takes much less to inactivate the remaining copy. Therefore, patients with inherited mutations often show increased risk and decreased age of onset of cancer. For example, inheriting one mutant copy of the TP53 tumor-suppressor gene often leads to Li-Fraumeni syndrome. Li-Fraumeni syndrome strongly predisposes a patient to develop cancer, which usually shows a very early age of onset, as well as the formation of multiple tumors throughout the life of the individual.

For example, BRCA1 is a tumor-suppressor gene encoding a protein whose normal function is to repair damaged DNA. Inheriting a mutation in BRCA1 significantly increases a woman’s risk of developing breast or ovarian cancer. This is because defects in BRCA1 function lead to the accumulation of additional mutations in the genome.

Acquired mutations: In addition to inheriting mutations, an individual can acquire changes in the genetic material over their lifetime. Each time a cell in the body divides, it must faithfully replicate its genetic material contained in the DNA. If the DNA is not correctly replicated, then mutations can arise, which, if left uncorrected, will be passed on to all daughter cells that descend from that cell. Because mutations are made each time the genome is replicated, the mutation rate within a cell depends on the fidelity of the machinery that recognizes and repairs these mutations.

In addition to acquiring unrepaired mutations that may occur each time a cell replicates its genetic material, genes can become mutated because of exposure to different mutagenic agents, or mutagens, originating from within the cell and toxins from the environment. By-products of cellular metabolism, such as reactive forms of oxygen, can cause DNA mutation. Chemical carcinogens, ionizing radiation, and viruses are all environmental agents that can generate mutations.

Mutagenesis in cancer cells: Cancer cells often show rates of mutation that are significantly higher than those of normal cells. This can be due to gene mutations normally involved in identifying and repairing mutations. If a mutation occurs in the DNA during replication or due to other damage, it is recognized by a set of proteins. These proteins signal the cell to stop dividing and recruit other proteins to repair the damage. If the damage is too severe, the cell will undergo programmed cell death or apoptosis. If DNA damage is not correctly identified and repaired, then this could lead to increased rates of mutation, ultimately leading to the accumulation of multiple genetic “hits” and the development of cancer.

Over time, the likelihood of mutations in proto-oncogenes or tumor-suppressor genes increases. Genetic testing is available to detect mutations in some of these commonly mutated genes, and knowledge of specific mutational status can provide important insight into prognosis and treatment.

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