16.4 Changes in Chromosome Number and Structure Are Often Associated with Cancer

Most tumors contain cells with chromosome mutations. For many years, geneticists argued about whether these chromosome mutations were the cause or the result of cancer. Some types of tumors are consistently associated with specific chromosome mutations; for example, most cases of chronic myelogenous leukemia are associated with a specific reciprocal translocation. These types of associations suggest that chromosome mutations contribute to the cause of the cancer. Yet many cancers are not associated with specific types of chromosome abnormalities, and individual gene mutations are now known to contribute to many types of cancer. Nevertheless, as we have noted, chromosome instability is a general feature of cancer cells. That instability causes them to accumulate chromosome mutations, which then affect individual genes that may contribute to the cancer process. Thus, chromosome mutations appear to be both a cause and a result of cancer.

At least three types of chromosome rearrangements—deletions, inversions, and translocations—are associated with certain types of cancer. Deletions can result in the loss of one or more tumor-suppressor genes. Inversions and translocations contribute to cancer in several ways. First, the chromosome breaks that accompany these mutations can lie within tumor-suppressor genes, disrupting their function and leading to cell proliferation.

Second, translocations and inversions can bring together sequences from two different genes, generating a fusion protein that stimulates some aspect of the cancer process. Fusion proteins are seen in most cases of chronic myelogenous leukemia, which affects bone-marrow cells. Most people with chronic myelogenous leukemia have a reciprocal translocation between the long arm of chromosome 22 and the tip of the long arm of chromosome 9 (Figure 16.9). This translocation produces a shortened chromosome 22, called the Philadelphia chromosome because it was first discovered in Philadelphia. At the end of a normal chromosome 9 is a potential cancer-causing gene called c-ABL. As a result of the translocation, part of the c-ABL gene is fused with the BCR gene from chromosome 22. The protein produced by this BCR–c-ABL fusion gene is much more active than the protein produced by the normal c-ABL gene; the fusion protein stimulates increased, unregulated cell division and eventually leads to leukemia.

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Figure 16.9: A reciprocal translocation between chromosomes 9 and 22 causes chronic myelogenous leukemia.

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A third mechanism by which chromosome rearrangements can produce cancer is the transfer of a potential cancer-causing gene to a new location, where it is activated by different regulatory sequences. Burkitt lymphoma is a cancer of the B cells, the lymphocytes that produce antibodies. Many people with Burkitt lymphoma possess a reciprocal translocation between chromosome 8 and chromosome 2, 14, or 22 (Figure 16.10). This translocation relocates a gene called c-MYC from the tip of chromosome 8 to a position on chromosome 2, 14, or 22 that is next to a gene that encodes an immunoglobulin protein. At this new location, c-MYC, a cancer-causing gene, comes under the control of regulatory sequences that normally activate the production of immunoglobulins, and c-MYC is therefore expressed in B cells. The c-MYC protein stimulates the division of the B cells and leads to Burkitt lymphoma.

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Figure 16.10: A reciprocal translocation between chromosomes 8 and 14 causes Burkitt lymphoma.

CONCEPTS

Many tumors contain a variety of types of chromosome mutations. Some types of tumors are associated with specific deletions, inversions, and translocations. Deletions can eliminate or inactivate genes that control the cell cycle; inversions and translocations can cause breaks in genes that suppress tumors, fuse genes to produce cancer-causing proteins, or move genes to new locations, where they are under the influence of different regulatory sequences.

CONCEPT CHECK 4

Chronic myelogenous leukemia is usually associated with which type of chromosome rearrangement?

  1. Duplication

  2. Deletion

  3. Inversion

  4. Translocation

d

Most advanced tumors contain cells that exhibit a dramatic variety of chromosome anomalies, including extra chromosomes, missing chromosomes, and chromosome rearrangements (Figure 16.11). Some cancer researchers believe that cancer is initiated when genetic changes take place that cause the genome to become unstable, generating numerous chromosome abnormalities that then alter the expression of oncogenes and tumor-suppressor genes.

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Figure 16.11: Cancer cells often possess chromosome abnormalities, including extra chromosomes, missing chromosomes, and chromosome rearrangements. Shown here are chromosomes from a colon-cancer cell, which has numerous chromosome abnormalities. For comparison, see a normal karyotype in Figure 2.5.
[Courtesy Dr. Peter Duesberg, UC Berkeley.]

A number of genes that contribute to genomic instability and lead to missing or extra chromosomes (aneuploidy) have now been identified. For example, mutations in genes that encode parts of the mitotic spindle apparatus may contribute to abnormal chromosome segregation and lead to chromosome abnormalities. The APC gene, as we have seen, is a tumor-suppressor gene that is often mutated in colon-cancer cells. This gene has several functions, one of which is to interact with the ends of the microtubules that associate with the kinetochore. Dividing mouse cells that have defective copies of the APC gene give rise to cells with many chromosome defects.