The genetic predisposition to cancer.
The multi-stage nature of cancer, and the interaction of the host and environment in the origin of cancer, both suggest multiple ways in which genetic predisposition to cancer might operate. A role for genetic variation has already been demonstrated in many instances and it is likely that still more examples of genetic predisposition will be uncovered. In some individuals genetic predisposition operates interactively with environment. Much of human cancer may occur in persons of this interactive oncodeme. Other persons have a very strong susceptibility to cancer because they have inherited a mutation on the path to cancer; they belong to a "purely" genetic oncodeme. The population of target cells itself is known to be affected by some environmental agents. Genetic factors may also operate, as in the X-linked lymphoproliferative syndrome with its predisposition to Burkitt lymphoma. Somatic mutation plays a critical role in carcinogenesis. Numerous environmental agents can increase the probability that somatic mutation will occur. Host genes can interact with these factors in two general ways. One concerns the ability to repair the damage caused by the agent. Most of the damage is repaired in normal persons, but much more is not repaired in persons with certain recessively inherited disorders, known as DNA-repair deficiencies. The other general way concerns the delivery of the critical agent. For example, the albino absorbs such excessive amounts of sunlight that even a normal DNA-repair mechanism is stressed. Similarly, some individuals metabolize certain chemical compounds in such a way that the concentration of an active mutagen is abnormally high, again overcoming the DNA-repair mechanism. The stages of promotion, progression, and metastasis are much less well understood, and clear examples of a role for genetic factors in them are not available. However, there are multiple ways in which heredity could be interacting, as with a genetic control of hormone production. Finally, the genetic targets of mutation, the "cancer genes," can play a role in cancer. Although no heritable mutations for oncogenes are yet known in man, there are reasons to believe that they could occur. On the other hand, heritable mutations of anti-oncogenes are well known and apparently account for much, or all, of dominantly heritable cancer in humans. In toto, the contribution of genetic predisposition to the burden of cancer could be considerable, because of the potentially large size of the interactive oncodeme. Identification of such susceptible persons could have important consequences in preventive oncology.(ABSTRACT TRUNCATED AT 250 WORDS)
Knudson
A G
AG
Fox Chase Cancer Center, Philadelphia, PA 19111.
D002471:Cell Transformation, Neoplastic / Q000139:chemically induced; D003043:Cocarcinogenesis; D004198:Disease Susceptibility; D004785:Environmental Pollutants / Q000009:adverse effects; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D009857:Oncogenes
D004785:Environmental Pollutants