Biomedical subjects
Publications and source records attributed to A G Knudson.
The chromosomal location of the rat interferon-alpha (IFNA) gene cluster was determined by fluorescence in situ hybridization. The fluorescent signals were localized to 5q31----q33. A previous report, using somatic cell hybrids, had suggested that the IFNA locus maps at a different region on rat chromosome 5.
The number of necessary oncogenic events is a function of tissue ontogeny. A minimum of two events appears to suffice for certain embryonal tumors, leukemias, and lymphomas for which the target tissues normally show stem cell proliferation. Other tumors, including those featured in the Li-Fraumeni syndrome, arise in target tissues whose stem cells are conditionally stimulated to proliferate, as in response to hormones, and involve more events. The most complex cancers include most carcinomas, which arise in renewal tissues whose stem cells do not normally proliferate. The number of necessary oncogenic events appears to increase with the number of controls on proliferation.
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The embryonal tumors of children occur in dominantly heritable and nonhereditary forms, which indicates that a dominant mutation can be on the carcinogenic pathway. A model which fits age-specific incidence hypothesizes that both forms arise as a consequence of two mutations. The background incidences of these tumors then reflect spontaneous mutation rates in germinal and somatic cells and may be increased by mutagens. The gene for one tumor (retinoblastoma) seems to be located on chromosome 13. Clues to the pathophysiology of these tumor genes come from consideration of their tissue specificity, origin from embryonal cells, and developmental effects. Childhood cancers may be manifestations of the homozygous states of a series of genes concerned with differentiation in specific embryonal tissues.
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The two-mutation theory of cancer initiation hypothesizes that some cancers originate after two successive mutations, of which the second mutation is always somatic and the first mutation may be germinal (hereditary cases) or somatic (nonhereditary cases). A quantitative model using the Poisson distribution is developed for ages at diagnosis for hereditary and nonhereditary cases. This model relates age-specific incidence data explicitly to the number of divisions of embryonal cells and to rates of somatic mutations per cell division. A good fit is obtained when the model is applied to data on ages at diagnosis for one such embryonal tumor, retinoblastoma.
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The risk of cancer can be increased by both genetic predisposition and environmental exposure. A common mechanism, mutation, may be involved in both. The rate of mutation in germ cells is the principal determinant of the incidence of genetically predisposed individuals, whereas the rate in somatic cells is the principal determinant in those not so predisposed. Many environmental carcinogens produce their effects via increased somatic mutation rates. The individuals of a population may be classified according to the operation of genetic predisposition, exposure to environmental carcinogens (mutagens), both, or neither. This last group reflects "background" somatic mutation rates.
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Case reports of neuroblastoma revealed that some individuals are genetically predisposed and that this genetic predisposition may have other consequences. According to a mutation model, two classes of individuals could acquire neuroblastoma. One (prezygotic) was a rare class that carried a dominant gene imparting high risk of the tumor. The other (postzygotic) comprised all other individuals, each at low risk. The model related tumor incidence to germinal and somatic mutation rates and thereby carried implications for environmental modification of tumorigenesis and demographic variation in incidence. Case reports also revealed associations of neuroblastoma with congenital defects and a susceptibility to second tumors. Analogy with retinoblastoma and Wilms' tumor of the kidney suggested that these associations could result from action of a neuroblastoma gene or from chromosomal aberration. One known dominantly inherited condition, von Recklinghausen's disease, could dispose to neuroblastoma and create some associations. According to the two-mutation model, neuroblastoma may have been a single recessive gene disorder at the level of the cell. The phenomena of aganglionosis, neuroblastoma in situ, maturation of neuroblastoma to ganglioneuroma, and spontaneous regression suggested that such a neuroblastoma gene interfered with normal developmental processes. The specificities of this gene and of those for von Recklinghausen's disease and pheochromocytoma suggested that the functiof a membrane macromolecule.
A consideration of the world-wide incidences of childhood cancer and of hereditary subgroups leads to the conclusion that two successive mutations can initiate cancer cells and that such cells usually proceed to develop into detectable cancers in a period of time which is short compared with the time required for most adult cancers. Environmental carcinogens could hypothetically increase the rates at which these mutations occur, but they probably, in fact, contribute little to the incidences. Certain exceptions, notably leukemia and lymphoma, are noteworthy, and a viral origin for them has been widely hypothesized. If most solid tumors of childhood are indeed correctly attributable to mutations in germ and/or somatic cells, then the prospect for the prevention of childhood cancer becomes very dim. In fact, the incidence of the germinal forms may increase as treatment improves (18). In theory, one might be able to identify individuals harboring cancer genes germinally and even to identify them prenatally. But even if the burden of cancer attributable to the hereditary subgroups were elimanted, there would still remain the larger nonhereditary group resulting from somatic mutations. If this hypothesis is correct, then childhood cancer cannot be prevented. With this conclusion goes the admonition, however, that environmental mutagens might significantly increase the burden of childhood cancer. One such mutagen, therapeutic radiation, is known to increase the prospect that second tumors will occur in patients who carry a germinal cancer mutation. The major effort to reduce the incidence of childhood cancer by prevention should be spent in examining the possibility that leukemia and lymphoma are viral in origin. If the arguments presented are correct, then the main effort against childhood cancer must be that of early diagnosis and treatment. I realize that many have already argued for that strategy in the approach to cancer generally, but I now believe that it is particularly relevant to any program against cancer in children.
Retinoblastoma should not be considered as the exceptional childhood cancer that shows dominant inheritance, but rather as the typical childhood cancer that embraces a prezygotic and postzygotic subgroup. Postzygotic cases are conceived as involving mutation as a first step too, but with the mutation in somatic rather than germinal cells. In both prezygotic and postzygotic cases a second event, possibly mutational, occurs before the cancer is initiated. The embryonal cancers are all visualized as genetic disease, and their frequencies limited by gene mutability. This mutability can be increased by environmental agents. Prezygotic cases may develop other primary tumors in other tissues. They may also have affected family members, the probability of affected offspring approaching 50%. A diagnostic test to identify prezygotic cases among those with a single primary tumor and a negative family history is sorely needed.
The incidences of some childhood cancers have been shown to fit a two-mutation hypothesis for cancer initiation. According to this hypothesis, the first mutation can be either germinal or somatic while the second is always somatic. A probabilistic model involving the mean number of tumors per genetically susceptible individual is developed as a function of age and is compared with age incidence data for retinoblastoma. The change in the mean number of tumors with time is interpreted in terms of the growth of retinal cells. In patients who are not genetically susceptible, the times of occurrence of the first and second somatic mutations can be inferred from a comparison of familial and non-familial unilateral case incidences. The total incidences of hereditary and nonhereditary forms of retinoblastoma are related to germinal and somatic mutation rates. The even distribution of certain childhood cancers throughout the world suggests that their incidences are determined by spontaneous mutation rates rather than by local environmental mutagenic carcinogens.
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