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CANCER: ONCOGENES

Oncogenes (literally 'cancer genes') were first discovered in the genetic material of viruses that are capable of causing cancers in animals. As the powerful tools of biology were applied to these viruses it became clear that particular genes within them were responsible for altering the cells in the animals that were infected. Although this finding was of great scientific importance, it was initially felt not to be central to the understanding of cancer in humans because viruses are unusual, and often only indirect, causes of cancer in man. The immediate importance of oncogenes in human cancer became clear with the discovery that most of the virus oncogenes had very close relatives that were present in the normal human cell. Moreover, these seem to be very important genes and there are close similarities between these genes in man and in other animals, including mice. When a particular kind of gene occurs in many, many species, this usually means that this type of gene is carrying out a very important function and that it has been conserved for that purpose by each species.

Oncogenes are present in normal cells where they do not cause cancer. In this situation they are called proto-oncogenes. The immediate question was: how do they cause cancer when a virus infects an animal cell? The answer lies in an alteration in the level of activity and the type of activity of such genes. It became clear that although these oncogenes would normally influence the control of cellular proliferation and differentiation in a beneficial and appropriate way, if they were altered so that the sequence of their DNA was slightly different, or if they became overactive because too many copies were present, or if they moved to the wrong part of the genetic material of the cell, then their activity would be disordered. This could result in disordered proliferation and hence contribute to the development of a cancer. Many dozens of oncogenes have now been discovered and it appears very likely that many of them are important in the cause of human cancer. This does not mean that the cancers in humans arise as a result of virus infection. Alterations in these genes can occur as a result of a number of processes and, once they are altered, they can contribute to the formation of the cancer. The virus link with cancer in animals allowed us to discover oncogenes. Overactivity and altered activity of an oncogene is commonly found in many human cancers although the same oncogene may not be altered in all cancers of one organ. Disorder of an oncogene is likely to be one or more of the steps in the creation of a fully fledged cancer and several powerful examples of this are now known for common cancers, including lung cancer and cancer of the bowel.

Each oncogene is now usually given a brief name derived from the virus in which it was first found or from some other feature of its description. The three-letter name is typical and important examples are ras, myc and sis.

We have referred to oncogenes as important elements controlling the behaviour of a cell and, in particular, its proliferation. How do they do this? The answers are still uncertain but many important clues are being revealed and this field of cancer research is one of those developing most rapidly. The functions of different oncogenes may be very different from each other but most of them seem to be involved in the process by which factors control the proliferation of cells.

Thus some oncogenes may provide the genetic information which leads to the manufacture of substances (receptors) on the surface of cells which receive signals instructing that cell to multiply. Some oncogenes may code for the substances within the cell that transmit signals from the surface into the nucleus of the cell where most of the genetic control is occurring. Other oncogenes code for factors which are attached to the nucleus or contained within it which presumably act as the final pathway by which the signals are transmitted into the important control centres. Yet others may actually code for the signalling substances themselves (usually called growth factors). Alterations at any one of these points can result in the wrong message being transferred into the cell telling it to continue proliferating when a normal cell would be switched off, resting and without potential to cause any harm. Alterations in the oncogenes which are responsible for each of these stages in the process of signalling into the cell can therefore contribute to the development of cancer.

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Cancer

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