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Identifying tumour suppressor genes

Enormous scientific progress has been made in recent years providing reasons to believe that our growing understanding of cancer will eventually allow it to be brought under control.

Tapan Kumar Maitra | New Delhi |

The term cancer, which means “crab” in Latin, was coined by Hippocrates in the fifth century BC to describe diseases in which tissues grow and spread unrestrained throughout the body, eventually choking life. Cancers can originate in almost any organ; depending on the cell type involved, they are grouped into several different categories.

Carcinomas, which account for about 90 per cent of all cancers, arise from the epithelial cells that cover external and internal body surfaces. Lung, breast, and colon cancer are the most frequent cancers of this type. Sarcomas develop from the cells of supporting tissues such as bone, cartilage, fat, connective tissue, and muscle. Finally, lymphomas and leukemias arise from cells of blood and lymphatic origin, with the term leukemia being reserved for situations in which the cancer cells reside and proliferate mainly in the bloodstream rather than growing as solid masses of tissue.

No matter where cancer arises, it is defined by a combination of two properties: the ability of cells to proliferate in an uncontrolled fashion and their ability to spread through the body. Anyone familiar with the events occurring inside living cells must feel a sense of awe at the complexities involved. Given the vast number of activities that need to be coordinated in every cell, it is not surprising that malfunctions occasionally arise. Cancer is a prominent example of a disease that arises from such abnormalities in cell function. If current trends continue, almost half the population of the United States will eventually develop cancer, making it the secondleading cause of death after cardiovascular disease.

The molecular and genetic defects that lead to cancer is not yet complete, enormous progress has been made in recent years and there is reason to believe that our growing understanding of this dreaded disease will eventually allow it to be brought under control. A large body of evidence points to the role played by DNA mutations in the development of cancer. Some cancer- causing mutations are triggered by chemicals and radiation, and some are caused by infectious agents.

Others simply represent spontaneous mutations, DNA replication errors, or in certain cases, inherited mutations. But in spite of these differences in origin, the final result is always the mutation of genes involved in controlling cell proliferation. The two main classes of affected genes are oncogenes and tumour suppressor genes. In contrast to oncogenes, whose presence can induce cancer formation, the loss or inactivation of tumour suppressor genes can also lead to cancer.

As the name implies, the normal function of such genes is to restrain cell proliferation. In other words, tumour suppressor genes act as brakes on the process of cell proliferation whereas oncogenes function as accelerators of cell proliferation. Of the roughly 30,000 genes in human cells, only a few dozen exhibit the properties of tumour suppressors. Since losing the function of just one of these genes may cause cancer, each must perform an extremely important function. The first indication that cells contain genes whose loss can lead to cancer came from cell fusion experiments in which normal cells were fused with cancer cells.

Based on our current understanding of oncogenes, you might expect that the hybrid cells created by fusing cancer cells with normal cells would have acquired oncogenes from the original cancer cell and would therefore exhibit uncontrolled growth, just like a cancer cell. In fact, this is not what happens. The fusion of cancer cells with normal cells almost always yields hybrid cells that behave like the normal parent and do not form tumours.

Such results, first reported in the late 1960s, provided the earliest evidence that normal cells contain genes that can suppress tumour growth and reestablish normal growth behaviour. Although fusing cancer cells with normal cells generally yields hybrid cells that lack the ability to form tumours, this does not mean that these cells are normal. When they are allowed to grow for extended periods in culture, the hybrid cells often revert to the malignant, uncontrolled behaviour of the original cancer cells. Reversion to malignant behaviour is associated with the loss of certain chromosomes, suggesting that these particular chromosomes contain genes that had been suppressing the ability to form tumours. Such observations eventually led to the naming of the lost genes as “tumour suppressor genes.”

As long as hybrid cells retain both sets of original chromosomesthat is, chromosomes derived from both the cancer cells and the normal cells-the ability to form tumours is suppressed. Tumour suppression is even observed when the original cancer cells possess an oncogene, such as a mutant RAS gene, that is actively expressed in the hybrid cells. This means that tumour suppressor genes located in the chromosomes of normal cells can overcome the effects of a RAS oncogene present in a cancer cell chromosome.

The ability to form tumours only reappears after the hybrid cell loses a chromosome containing a critical tumour suppressor gene. Although cell fusion experiments provided the initial evidence for the existence of tumour suppressor genes, identifying these genes is not a simple task. By definition, the existence of a tumour suppressor gene only becomes evident after its function has been lost.

How do scientists go about finding something whose very existence is unknown until it disappears? One approach involves families that are at high risk for developing cancer. While most cancers are known to be environmentally triggered, about 10-20 per cent of cancer cases can be traced to inherited gene defects. When it is said that such cancers are hereditary, this does not mean that people actually inherit cancer from their parents. What can be inherited, however, is an increased susceptibility to developing cancer.

The reason for the increased risk is usually an inherited defect in a tumour suppressor gene. Since tumour suppressor genes are entities whose loss of function is associated with cancer, two successive mutations are typically required-one in each copy of the gene carried on two homologous chromosomes. The chances of two such mutations occurring: randomly in the two copies of the same gene is very small. However, if people inherit a mutant (or missing) version of a particular tumour suppressor gene from one parent, they are at much higher risk of developing cancer because only one mutation (in the second copy of that tumour suppressor gene) in a single cell is now needed to cause cancer.