GENETIC CHANGES IN CANCER CELLS

Most cancers are caused by mutations of genes within somatic cells. When DNA is replicated prior to cell division, a small number of replication errors occur in which the nucleotide sequence in the replicated DNA is different from the original DNA. A DNA sequence, with replication errors in it, is a mutation. Factors such as radiation, certain chemicals and toxins, and some viruses also cause mutations because they damage or alter DNA. Because mutations are most likely to occur during DNA replication, cancer usually develops in tissues that are undergoing frequent cell divisions. If mutations affect genes that regulate cell divisions, and if the result is uncontrolled cell divisions, a neoplasm can be produced. A neoplasm can become cancer if additional mutations change the structure and function of its cells. For example, some mutations increase the ability of cancer cells to invade and destroy surrounding tissues, some mutations allow cancer cells to metastasize, and some mutations make cancer cells resistant to drug treatments, such as the drugs used in chemotherapy.

Two major mechanisms help prevent the development of cancer in cells:

?(1) DNA repair enzymes detect and correct errors that occur during replication and

(2) a self-destruction mechanism destroys cells with abnormal DNA. Apoptosis (apop-tosis) is a process by which cells self destruct. Many cells, such as epithelial cells, have a limited life span, whereas others, such as neurons and skeletal muscle cells last a lifetime. Apoptosis is a normal process involved in the self-destruction of cells that have a limited life span. Apoptosis can also cause self destruction in cells with damaged DNA. Therefore, apoptosis can cause self-destruction in cells with mutations, and apoptosis can, therefore, remove cells with mutations before cancer develops. The likelihood that cancer will develop is increased if the genes controlling DNA repair enzymes undergo mutations, resulting in defective DNA repair enzymes, so that mutated genes persist in cells. Mutation of genes responsible for apoptosis can also result in the persistence of cells with mutations, and these cells can continue to divide. Because mutations are most likely to occur when DNA replicates, mutations leading to cancer are most likely to occur in cells undergoing cell division, such as rapidly dividing epithelial cells, rather than in non-dividing cells, such as in skeletal muscle cells and neurons.

Cancer develops in somatic cells because of mutations that occur during cell divisions. Therefore, few cancers are inherited. Approximately 10% of human cancers, however, are inherited because of an increased genetic susceptibility to cancer. For example, a person can inherit a normal allele and a mutated allele for a regulatory gene that is involved in the development of cancer. As long as the normal allele functions, the effect of the mutated allele is masked. However, if the normal allele mutates during cell division of a somatic tissue, expression of the allele involved in the development of cancer can be expressed.

Compared with a person with two normal alleles for a regulatory gene involved in the development of cancer, a person with a genetic susceptibility for cancer is much more likely to develop cancer because only one allele has to mutate, instead of two. Certain kinds of colon cancers and breast cancers are examples of genetic susceptibility to cancer. The accumulation of mutations resulting in cancer occurs over many generations of cells and may require several years to develop. This is one reason that cancer becomes more common in people as they become older.

Once a mutation alters a gene in a cell, that altered gene can be passed to the daughter cells when the parent cell undergoes cell division. For cells that survive and undergo cell division, altered genes are passed to all of the offspring of the original cell in which the mutation occurred. For example, a single mutation may cause a cell to undergo cell division at an increased rate. This mutation is passed to the offspring of that cell.

Another mutation may occur in one of these cells and it, along with the original mutation, is passed to its offspring. In this fashion, mutations responsible for the development of cancer accumulate in cells. Therefore, cancer is polygenic .

Some genes promote cell division, whereas others suppress it. Genes that promote cell division are called proto-oncogenes. Mutations in proto-oncogenes can give rise to abnormal regulatory genes, called oncogenes (ongkojenz), which increase the rate of cell division.

Oncogenes can code for growth factors, growth factor receptors, or chemical signals that control cell divisions. Many types of oncogenes have been identified in human cancers. Tumor suppressor genes are normal genes that slow or stop cell division. Mutations that delete or inactivate tumor suppressor genes can also increase the rate of cell division by taking off the brakes, so to speak, of the processes that promote cell division. Many altered tumor suppressor genes have been identified in human cancer cells.

Additional mutations cause the structure and functions of the cancer cells to differ from those of normal cells. For example, these mutations increase the ability of cancer cells to invade and destroy surrounding tissues and to metastasize. The continued accumulation of mutations in cancer cells is also responsible for changes in the characteristics of the cancer cells over time. These changes can result in cancer cells in a tumor becoming less sensitive to treatment designed to kill the cancer cells. Some mutations help make cancer cells less sensitive to chemotherapeutic drugs.