Chromosomes and cancer

ALSO KNOWN AS: Chromosomal instability, CIN

DEFINITION: Cancer typically results from a series of mutations in two classes of genes: oncogenes and tumor suppressors. Cancer cells typically exhibit broader changes to their chromosome structure that extend well beyond the deoxyribonucleic acid (DNA) base changes that accompany most mutations. These include changes in chromosome number and the deletion, duplication, inversion, and translocation of chromosomal segments. Chromosomal aberrations have historically been more challenging to study than genetic mutations, and no direct evidence of their role in carcinogenesis has been produced. Scientists continue to debate whether these chromosomal changes play a causal role in cancer or are simply an artifact of the mutations that lead to cancerous states. However, some consensus has been reached that mutations and chromosomal instability probably play complementary roles in cancer formation and that neither acts completely independently of the other.

Etiology and symptoms of associated cancers: Most cancer cells are aneuploid. Aneuploidy is the term used to describe the gain or loss of a chromosome in a cell, whether it be an entire chromosome or just a portion of one. In the latter case, the gain can also be described as insertion or duplication, depending on whether the chromosome portion comes from another chromosome or is duplicated from within the same chromosome, and the loss is also known as deletion. Unlike single mutations, aneuploidy can affect the expression of genes by the thousands, as large numbers of genes have their expression effectively doubled or cut in half by the insertion or deletion, respectively, of a chromosomal segment. Such changes in a gene’s “dosage” may, in turn, lead to an increased rate of cellular mutation, especially if the affected genes are involved in the repair of DNA damage. Aneuploidy and mutation can be considered complementary processes, with one state often leading to the other.

Polyploidy, an extreme form of aneuploidy, plays a significant role in the formation of solid tumors. In this condition, a cell's entire complement of chromosomes is duplicated, resulting in more than the usual two copies of each chromosome. This phenomenon is commonly observed in many solid tumors. Additionally, subtler changes in gene expression can also result from two other chromosomal aberrations in cancer cells. The first is inversion, where a chromosomal segment is 'flipped around' in a chromosome. The second is translocation, where the segment is transferred to a different chromosome. Although the genes on this segment are still present in the cell, they may be differentially expressed because the precise location of a gene on a chromosome often affects its activity level.

The evidence supporting a causative relationship between aneuploidy and cancer is compelling. Aneuploid cells are associated with certain precancerous lesions, indicating that they cannot have been caused by the formation of a cancerous state. Specific chromosomal translocationsoften referred to as marker chromosomesare diagnostic of certain forms of cancer. Furthermore, the degree of aneuploidy in a cancer cell often correlates with the severity of the disease and can even be predictive of clinical outcomes. Aneuploidy has also been suggested to be one of the reasons cancer cells are so well adapted for continuous growth in their particular environment. By displaying a nearly limitless number of phenotypes that result from changing the dosage of many different combinations of genes, those cells that are particularly well adapted will be selected for and will propagate more cells like themselves. However, there remains no direct evidence that an aneuploid state causes the cellular changes that lead to cancer.

Another chromosomal abnormality associated with almost all cancer cells, but which was not evident initially using conventional cytological techniques, is the presence of very short telomeres. Telomeres are arrays of repetitive DNA that are found on the ends of linear chromosomes. These structures protect genomic DNA from the shrinkage that occurs in chromosomes every time they are replicated. DNA polymerase, the enzyme used to copy DNA, cannot copy a complete linear molecule of DNA due to its use of a ribonucleic acid (RNA) "primer" to initiate its activity. Therefore, Telomeres are degraded each time a cell duplicates and divides, limiting the number of divisions any cell can undergo. Rapidly dividing cells, such as those associated with cancer, quickly reach this limit and enter a stage known as cellular crisis. Most cells that reach this stage stop dividing, and many die. Still, cancerous cells overcome this limitation, called the Hayflick limit, after American cell biologist Leonard Hayflick first described this phenomenon in 1962. Most cancer cells express an enzyme called telomerase, which adds DNA repeats to the ends of the chromosomes, thus allowing cells to continue dividing indefinitely.

Shortened telomeres are associated with chromosomal instability. Telomeres in this shortened state often fuse or to other regions of double-stranded breaks within chromosomes to avoid further degradation. The number of such break sites in cancer cells frequently increases because of mutations in the DNA enzymes used to repair such damage. Chromosomes fused end-to-end or to another chromosomal segment containing a centromere are then further jumbled when their DNA is pulled apart during mitosis. The centromere is a region of DNA that typically makes up the center of a chromosome and is the area to which the mitotic spindle attaches when sister chromosomes are separated from one another. The chromosomal abnormalities associated with aneuploidy can result from such cycles of fusion followed by chromosomal breakage.

History: The idea that cancer is a chromosomal disease is not new. In 1902, Theodor Boveri, a German zoologist, proposed that changes in chromosome number were the cause of tumor formation. He used cytological techniques to view the chromosomes of a tumor cell using a microscope. This is not to say that his aneuploidy theory did not leave room to account for the contributions of changes to specific genes. As the concept of the gene began to take shape during the early twentieth century, Boveri formulated a theory of how aneuploidy caused cancer that incorporated an early notion of mutational changes. He proposed that abnormal mitoses could lead to a combination of "chromatin determinants" that would, in turn, lead to cancer.

However, when oncogenes and tumor suppressors were discovered in the 1970s and 1980s, the idea of aneuploidy as the causative factor of cancer began to fall out of favor. The notion that identifying specific mutations in a finite number of genes would lead to a complete understanding of cancer was appealing. As more cancer-causing genes were identified, the goal of understanding cancer at a molecular level seemed attainable. However, as time progressed, the mutational theory failed to explain several observations, including the rarity of cancer in newborns, something one would not predict if newborns inherited cancer-causing genes from their parentsthe fact that certain carcinogens are known to cause cancer without causing mutations and the fact that a long latency period is always present before cancer develops, even after exposure to fast-acting mutagens.

The resurgence of the aneuploidy theory of cancer formation can also be linked to the development of new techniques in the 1990s, such as microarrays, which allow the expression levels of many genes to be assayed simultaneously. Using microarray analysis, cancers exhibited changes in hundreds or even thousands of genes, many more than could be accounted for by a purely mutational model. As cancer research progresses, the role of both mutations and chromosomal aberrations will need to be taken into account to fully understand their contributions to carcinogenesis.

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