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A G Knudson

Publications and source records attributed to A G Knudson.

At least 55 records · Page 3Linked to original sources
PubMed1989

The ninth Gordon Hamilton-Fairley memorial lecture. Hereditary cancers: clues to mechanisms of carcinogenesis.

The study of hereditary cancer in humans, notably retinoblastoma, has identified a category of cancer genes that is different from that of the oncogenes. Whereas the latter group of genes exerts its effect through expression, the former does so as a result of failure of normal expression. Primary oncogene abnormality seems to play a crucial initiating role in certain neoplasms, particularly leukaemias, lymphomas and some sarcomas. In contrast, anti-oncogenes (tumour suppressor genes) appear to be important in the initiation of several solid tumours of children, as well as some common carcinomas of adults. Both classes are apparently involved in tumour progression and metastasis. Virtually every kind of cancer can occur in hereditary form, so the role of anti-oncogenes in the origin of human cancers may be considerable. The prototypic anti-oncogene has been that for retinoblastoma. For this tumour the recessive mechanism has been demonstrated by molecular means, and the gene has been cloned. The possibility has been suggested that gene (or gene product) replacement therapy could be accomplished.

Adult↗
PubMed1989

Nakahara memorial lecture. Hereditary cancer, oncogenes, and anti-oncogenes.

Dominantly heritable predisposition to cancer is well known, even if rare. Such heritable cases are known for most cancers. Predisposition is usually to one or a few specific cancers, and the kinds of pedigrees that are found suggest the existence of an array of 50 or so such cancer genes. Penetrance is usually high, as is the relative risk for a particular tumor. The inherited event is insufficient to cause cancer; at least one other (somatic) event must occur. For one tumor, retinoblastoma, the total number of necessary events seems to be two for both the hereditary and non-hereditary forms, and those events involve mutation or loss of the two copies of a tumor suppressor gene on chromosome 13. Analyses of tumors with polymorphic syntenic DNA probes and for abnormality of the gene itself have provided a picture of the kinds of first and second events that can occur. Several other tumors may follow the retinoblastoma scenario, including tumors associated with multiple endocrine neoplasia type 1 and with neurofibromatosis type 2, and identify the loci of several other putative anti-oncogenes. Still other hereditary cancer genes have been mapped, but evidence that they are suppressor genes is incomplete. It is possible that the inherited mutation may sometimes occur in an oncogene, although no such cases have been validated. In most, perhaps all, tumors, further genetic changes occur. In some instances these appear to be in oncogenes, and sometimes in anti-oncogenes. Some of these events appear to play a role similar to that of promotion in experimental carcinogenesis, whereas others are clearly important in progression. The process is particularly complicated in some of the common carcinomas, where changes in both oncogenes and anti-oncogenes are common.

Carcinoma, Renal Cell↗
PubMed1989

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)

Cell Transformation, Neoplastic↗
PubMed1988

The genetics of childhood cancer.

Two classes of genes are apparently critical in the origin of the cancers of children. One class, that of oncogenes, acts by virtue of abnormal or elevated activity. It is operative primarily in leukemias and lymphomas. There is no evidence yet that genetic predisposition to these neoplasms can be imparted by oncogene mutations in the germline. However, there are conditions that predispose to these tumors, primarily through excessive chromosomal breakage and rearrangement. The other class, that of anti-oncogenes, is recessive in oncogenesis; cancer results when both normal copies have been mutated or deleted. Some persons carry one such mutation in the germline and are highly susceptible to tumor because only one somatic event is necessary. Some children, even though carrying no such mutation in the germline, can acquire tumor as a result of two somatic events. Most solid tumors in children seem to involve initiation through the loss of both copies of an anti-oncogene.

Child↗
PubMed1987

Prince Takamatsu memorial lecture. Rare cancers: clues to genetic mechanisms.

Virtually every kind of cancer can occur in hereditary form. Such hereditary cancers are rare, but have been informative out of proportion to their frequencies because some of them have illuminated mechanisms important in the genesis of cancer generally. The prototypes of hereditary cancer have been two uncommon tumors, retinoblastoma and Wilms' tumor. Genetic epidemiologic analysis of these tumors led to the formulation of a model for their origin following two events. According to this model the first event could already be present in the germline, thereby giving rise to the heritable forms of these diseases; the second event would occur somatically in one or more cells of the relevant organ. Both events would occur somatically in the non-hereditary form. It was proposed that the two events involved mutation or loss of both copies of a particular gene; i.e., these genes are recessive in oncogenesis. Cytogenetic analyses of rare deletion cases of retinoblastoma permitted the localization of the retinoblastoma gene to chromosomal band 13q14. Deletion was also proposed as the mechanism for the rare conjunction of Wilms' tumor and aniridia; deletions of chromosomal band 11p13 were subsequently found. Deletions were also found in tumor cells of some patients with the non-hereditary forms of these two tumors, lending support to the idea that the same loci were involved in the two forms. The application of molecular genetic techniques led to verification of the recessive hypothesis for both retinoblastoma and Wilms' tumor and to the cloning of the gene of the former. These accomplishments are leading to a new understanding of mechanisms of oncogenesis and their involvement even in the common cancers of adults.

Child↗
PubMed1986

Genetics of human cancer.

Study of hereditary cancer in humans has revealed new mechanisms in carcinogenesis. In particular, a new class of cancer gene, recessive in oncogenesis, accounts for dominantly transmitted predisposition to some cancers, and may play a primary role in the nonhereditary forms of most cancers. Comparison of polymorphic markers in lymphocytes and tumors has permitted the in vivo observation of somatic events that lead to genetic recombination. The tissue specificities of these recessive cancer genes suggest that their normal alleles, like those of oncogenes, play important roles in normal development.

Chromosome Aberrations↗
PubMed1984

Genetic predisposition to cancer.

A minor fraction of cancer occurs in persons who have strong dominantly transmissible genetic predisposition. Retinoblastoma and Wilms' tumor are the most thoroughly studied examples. Hereditary cases involve mutations at the same chromosomal sites. In most carriers of mutation the change cannot be visualized; in some, it is a visible deletion. A significant fraction of nonhereditary cases involve deletion at the same site in tumor cells only, suggesting that mutation at this site is necessary for the initiation of tumor, whether hereditary or not. This may be a general model for human cancer. The initiating mutation is not sufficient, however, since only rare cells are transformed. A second event may be genetic, such that recessive loss of the gene occurs. A two-event genetic model for a major fraction of human cancers is also compatible with the well-established, age-specific incidence of various cancers.

Bloom Syndrome↗
PubMed1983

Cancer genes in man.

We may conclude, from all of these considerations, that the burden of cancer falls unequally upon a population of individuals. Some normal persons develop cancer as a result of bad luck; they are victims of spontaneous processes or background processes such as gene mutation or chromosomal rearrangement. Others are susceptible because they are exposed to environmental agents that increase these background rates. But there are individuals who are predisposed to cancer because they carry mutations that are already on the path to cancer or carry genes that increase the prospect that such mutation will occur, either spontaneously or in response to an environmental agent. It is even possible that most environmental cancer also involves genetic predisposition.

Ataxia Telangiectasia↗
PubMed1981

Mutation and cancer: a model for human carcinogenesis.

A model for carcinogenesis is presented that provides a framework for understanding the roles of "spontaneous" events, hereditary factors, and environmental agents in human carcinogenesis and for interpreting experimental carcinogenesis. This model incorporates two features: a) transition of target stem cells into cancer cells via an intermediate stage in two irreversible steps, and b) growth and differentiation of normal target and intermediate cells. Cast in mathematical terms, the model can be fitted to age-specific incidence data on human cancers of both children and adults and can illuminate the relative importance of agents that affect transition rates, tissue growth, and tissue differentiation. This is illustrated by application of the model to a) the epidemiology of lung cancer with emphasis on the role of cigarette smoking and b) the epidemiology of breast cancer with emphasis on the roles of hormones, radiation, and hereditary. The nature of the two events and of the intermediate stage is considered in light of hereditary conditions that predispose to cancer in humans. The modes of action of radiation and chemicals in carcinogenesis are discussed, as are predictions based on the model and amenable to experimental verification.

Adult↗
PubMed1980

Genetics and cancer.

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Carcinogens, Environmental↗