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Genetics and Cancer
VOLUME
The
American
Journal
69
NUMBER
1
JULY
1980
of Medicine@ EDITORIALS
Genetics and Cancer ALFRED
G. KNUDSON,
During the past decade familial cancer has attracted the attention of both physician and scientist. Even in the last century it was recognized that polyposis coli and colon cancer were heritable together, and not long after the rediscovery of Mendel it was clear that polyposis, von Recklinghausen’s disease, the family cancer syndrome of Warthin, and some cases of retinoblastoma were inherited in mendelian dominant fashion. For the most part, however, these rare conditions were viewed as curiosities whose study contributed little either to the prevention of cancer or to its understanding. Some events of the past decade have changed that view, even as a renewed interest in environmental carcinogenesis has emerged. The list of dominantly inherited cancer-predisposing states has grown considerably and includes such well known conditions as the nevoid basal cell carcinoma syndrome and the multiple endocrine neoplasia syndromes, and such diverse partially defined entities as the familial forms of breast cancer, leukemias and lymphomas, brain tumors and Wilms’ tumor. The definition of these states is easiest when penetrance is very high for the tumor itself, as with retinoblastoma, or for associated phenotypic effects, as with polyposis coli. It is most difficult when there is low penetrance for tumor and absence of other effect; in fact, a dominant gene that causes tumor in only 10 per cent of its carriers would remain unrecognized. Even so, there is at least one dominantly inherited form of many cancers and it would hardly be surprising to discover 100 to 200 such “cancer” genes in the human genomic lexicon. A different kind of hereditary predisposition to cancer has captured the attention of all cancer investigators during the past decade. This is the recessively inherited xeroderma pigmentosum, a fine example that destroys the idea that disease can be attributed to nature or to nurture. Although the fundamental defect is still not known in the precise terms of molecular genetics, it is
Jr., M.D., Ph.D. known that the ultraviolet light that causes skin cancer so readily in these patients also produces unrepaired or misrepaired damage in DNA at a much higher rate than is normal [l]. We may reasonably assume that some of these lesions are produced in genes that specify some regulatory function in skin cells. Ultraviolet light produces mutations in the somatic cells of these subjects at a higher rate than in normal persons; when one of a set of specific “skin cancer genes” is the target, skin cancer results. In this disease, cancer results from somatic mutation induced by an environmental agent in a genetically predisposed individual. No other example of genetic predisposition to environmentally-induced cancer has been so elucidated, but there are some other recessive conditions that seem related. Clinical reports of radiosensitivity of patients with ataxia telangiectasia led to the discovery of an impaired ability to repair some kinds of damage to DNA caused by ionizing radiation [2]. This defect is associated with a predisposition to chromosomal breakage, to certain kinds of immunodeficiency and to lymphoreticular, and possibly other, neoplasias. Since chromosomal breakage is commonly found in the blood cells of these patients, it may be that ionizing radiation is not always the instrument of damage. In fact, some chemical agents can also induce breaks in vitro. The mechanism for producing immune deficiency is not known, but it does appear that the lymphoreticular neoplasias develop in lymphoid cells that have sustained a break at a specific point in the long arm of chromosome 14. Since the long arm of this chromosome is also the site of abnormality in some lymphoreticular neoplasias that are not associated with ataxia telangiectasia, it is likely that it contains a gene or genes specific for lymphoreticular differentiation and function, and that such genes can be the targets of somatic mutation under diverse circumstances. These are rare examples of genetic susceptibility to
From the Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. Requests for reprints should be addressed to Dr. Alfred G. Knudson, The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. This study was supported in part by an appropriation from the Commonwealth of Pennsylvania and by grant CA-06927 from the National Cancer Institute.
July 1966
The American Journal of Medicine
Volume 69
1
EDITORIAL-KNUDSON
TABLE I
Hereditary and Environmental Factors in the Origin of Cancer HMlltar)r
Cl&SS
Factors
Envkonmental Factors
C-
+ -
These are the so-called familial cancers These together comprise all environmental cancers
+
These are the “background” cancers
environmental carcinogens and contribute in a very small way to the total cancer burden, But there may be more common instances of such susceptibility. The gene for ataxia telangiectasia itself may afford an example. Swift et al. [3] have reported that the far more common heterozygotes of this gene (about 1 per cent of all individuals) may be unusually susceptible to cancer. Furthermore, there is good reason, from animal studies, to suspect that cancer is much more likely to develop in some apparently normal persons than in others upon exposure to certain proximate carcinogens, such as those found in cigarette smoke, because their cells harbor the necessary metabolic processes for activation to ultimate carcinogens. Although the results of a study of patients with lung cancer cannot be substantiated [4,5], it is still likely that individual variation of this kind plays a role in carcinogenesis. We do not yet know what fraction of cancer results from the interaction of genetic and environmental factors. We have seen a strong inclination in recent times to ascribe some major burden of the world’s cancer to environmental agents. This idea is based upon the great international variations observed for the common cancers and, particularly, upon migrant studies. In some instances we even have conclusive or promising evidence regarding the nature of some of these agents-the Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma), the hepatitis B virus (hepatocellular carcinoma), betel nuts (esophageal carcinoma), cigarette smoking (lung, bladder and some other cancers], and animal fat (colon and breast cancer). Yet we find that all of the major cancers occur in all countries and it, therefore, becomes unlikely that elimination of these environmental agents will eradicate cancer. There seems to be some “background” level of each cancer worldwide. Cancer can evidently occur in persons who have neither genetically nor environmentally imposed risk. We can, therefore, classify cancers broadly (Table I] with respect to their causation [6]. What is the mechanism that accounts for “background” cancers? If it is true that most environmental carcinogenesis is mediated via mutation in somatic cells, and if the dominantly heritable familial cancers are attributable to germinal mutations, then a natural hypothesis is that the background incidence of cancer is caused by “spontaneous” mutation in somatic cells. Spontaneous mutations are best known, and most readily demonstrated as mutations, when they occur in germ cells. But they also occur in somatic cells and are
2
July 1980
The American Journal of Medicine
Volume 69
widely regarded as playing a major role in carcinogenesis. Environmental mutagens/carcinogens can increase the rate at which somatic mutations occur. The genes that are mutated are probably the same in both the spontaneous and induced forms of a given cancer, although the molecular changes in DNA are sometimes different. Cancer will develop when a “cancer gene” is mutated in a cell that is able to express the mutation. These “cancer genes” may well be the same ones that have undergone mutation in germ cells to give rise to the dominantly inherited familial cancers; a specific cancer may result from mutation regardless of “cause,” and that mutation may be at the same genetic site in each instance. This is a hypothesis to be tested. A consequence of this hypothesis is that identification and characterization of the genes responsible for familial cancer would be at the same time an identification and characterization of the genes that are altered in “environmental” and “background” cancers. Anything learned about the correction of these gene defects might find application to all cancer. The genetic cancers would have an importance well beyond their incidence in the general population. Great progress has been made in the past few years towards the identification of human cancer genes, largely as the result of the powerful chromosomal banding techniques introduced early in the past decade. For two tumors, retinoblastoma and Wilms’ tumor, there are genetic forms in which a specific chromosomal deletion is present in every somatic cell; the defect is a visible germinal mutation [7,8]. The deletion imposes an exceedingly high risk for a site-specific tumor, just as occurs with the more usual dominantly heritable genes in which no chromosomal abnormality is apparent in normal somatic cells. A new cytogenetic technique introduced by Yunis and Ramsay [7] is capable of revealing subtle aberrations and will undoubtedly lead to the demonstration of more deletion cases that are not apparent with standard techniques. Cytogenetic analysis should also be able to verify the assertion that similar specific chromosomal aberrations are present only in tumor cells in nonhereditary cases and so substantiate the notion that a specific cancer can result from germinal or somatic mutation at a particular gene site
kc
Let us assume that some 100 to 200 cancer genes can be identified. They may have similar functions in that each is important for differentiation in a specific tissue.
EDITORIAL-KNUDSON
Ability to detect cells (lymphocytes or fibroblasts] that bear these genes could lead to the means for identifying persons at high risk; explication of the molecular defects associated with these mutations could advance our understanding of the fundamental defects in cancer cells and of the means for correcting them. For these reasons, familial cancer should continue to attract the attention of both physician and scientist.
REFERENCES 1. 2.
Cleaver JE, Bootsma D: Xeroderma pigmentosum. Annu Rev Genet 1975; 9: 19-38. Paterson MC, Smith PJ: Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing ra-
diation and related DNA-damaging chemicals. Annu Rev Genet 1979; 13: 291-318. 3. Swift M, Sholman L, Perry M, et al.: Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res 1976; 36: 209-215. 4. Kellermann G. Shaw CR, Luyten-Kellermann M: Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N Engl Med 1973; 289: 934-936. 5. Paigen B. Gurtoo HL, Minowada J. et al.: Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk. N Engl J Med 1977: 297: 346-350. 6. Knudson AG: Genetics and etiology of human cancer. Adv Hum Genet 1977; 8: l-66. 7. Yunis JJ, Ramsay N: Retinoblastoma and subband deletion of chromosome 13. Am J Dis Child 1978; 132: 161-163. 8. Francke U, Holmes LB, Atkins L. et al.: Aniridia-Wilms’ tumor association: evidence for specific deletion of 11~13. Cytogenet Cell Genet 1979; 24: 183-192. 9. Knudson AG: Retinoblastoma: a prototypic hereditary neoplasm. Semin Oncol1978; 5: 57-60.
July 1666
The American Journal of Medicine
Volume 66
3
The
American
Journal
69
NUMBER
1
JULY
1980
of Medicine@ EDITORIALS
Genetics and Cancer ALFRED
G. KNUDSON,
During the past decade familial cancer has attracted the attention of both physician and scientist. Even in the last century it was recognized that polyposis coli and colon cancer were heritable together, and not long after the rediscovery of Mendel it was clear that polyposis, von Recklinghausen’s disease, the family cancer syndrome of Warthin, and some cases of retinoblastoma were inherited in mendelian dominant fashion. For the most part, however, these rare conditions were viewed as curiosities whose study contributed little either to the prevention of cancer or to its understanding. Some events of the past decade have changed that view, even as a renewed interest in environmental carcinogenesis has emerged. The list of dominantly inherited cancer-predisposing states has grown considerably and includes such well known conditions as the nevoid basal cell carcinoma syndrome and the multiple endocrine neoplasia syndromes, and such diverse partially defined entities as the familial forms of breast cancer, leukemias and lymphomas, brain tumors and Wilms’ tumor. The definition of these states is easiest when penetrance is very high for the tumor itself, as with retinoblastoma, or for associated phenotypic effects, as with polyposis coli. It is most difficult when there is low penetrance for tumor and absence of other effect; in fact, a dominant gene that causes tumor in only 10 per cent of its carriers would remain unrecognized. Even so, there is at least one dominantly inherited form of many cancers and it would hardly be surprising to discover 100 to 200 such “cancer” genes in the human genomic lexicon. A different kind of hereditary predisposition to cancer has captured the attention of all cancer investigators during the past decade. This is the recessively inherited xeroderma pigmentosum, a fine example that destroys the idea that disease can be attributed to nature or to nurture. Although the fundamental defect is still not known in the precise terms of molecular genetics, it is
Jr., M.D., Ph.D. known that the ultraviolet light that causes skin cancer so readily in these patients also produces unrepaired or misrepaired damage in DNA at a much higher rate than is normal [l]. We may reasonably assume that some of these lesions are produced in genes that specify some regulatory function in skin cells. Ultraviolet light produces mutations in the somatic cells of these subjects at a higher rate than in normal persons; when one of a set of specific “skin cancer genes” is the target, skin cancer results. In this disease, cancer results from somatic mutation induced by an environmental agent in a genetically predisposed individual. No other example of genetic predisposition to environmentally-induced cancer has been so elucidated, but there are some other recessive conditions that seem related. Clinical reports of radiosensitivity of patients with ataxia telangiectasia led to the discovery of an impaired ability to repair some kinds of damage to DNA caused by ionizing radiation [2]. This defect is associated with a predisposition to chromosomal breakage, to certain kinds of immunodeficiency and to lymphoreticular, and possibly other, neoplasias. Since chromosomal breakage is commonly found in the blood cells of these patients, it may be that ionizing radiation is not always the instrument of damage. In fact, some chemical agents can also induce breaks in vitro. The mechanism for producing immune deficiency is not known, but it does appear that the lymphoreticular neoplasias develop in lymphoid cells that have sustained a break at a specific point in the long arm of chromosome 14. Since the long arm of this chromosome is also the site of abnormality in some lymphoreticular neoplasias that are not associated with ataxia telangiectasia, it is likely that it contains a gene or genes specific for lymphoreticular differentiation and function, and that such genes can be the targets of somatic mutation under diverse circumstances. These are rare examples of genetic susceptibility to
From the Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. Requests for reprints should be addressed to Dr. Alfred G. Knudson, The Institute for Cancer Research, The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111. This study was supported in part by an appropriation from the Commonwealth of Pennsylvania and by grant CA-06927 from the National Cancer Institute.
July 1966
The American Journal of Medicine
Volume 69
1
EDITORIAL-KNUDSON
TABLE I
Hereditary and Environmental Factors in the Origin of Cancer HMlltar)r
Cl&SS
Factors
Envkonmental Factors
C-
+ -
These are the so-called familial cancers These together comprise all environmental cancers
+
These are the “background” cancers
environmental carcinogens and contribute in a very small way to the total cancer burden, But there may be more common instances of such susceptibility. The gene for ataxia telangiectasia itself may afford an example. Swift et al. [3] have reported that the far more common heterozygotes of this gene (about 1 per cent of all individuals) may be unusually susceptible to cancer. Furthermore, there is good reason, from animal studies, to suspect that cancer is much more likely to develop in some apparently normal persons than in others upon exposure to certain proximate carcinogens, such as those found in cigarette smoke, because their cells harbor the necessary metabolic processes for activation to ultimate carcinogens. Although the results of a study of patients with lung cancer cannot be substantiated [4,5], it is still likely that individual variation of this kind plays a role in carcinogenesis. We do not yet know what fraction of cancer results from the interaction of genetic and environmental factors. We have seen a strong inclination in recent times to ascribe some major burden of the world’s cancer to environmental agents. This idea is based upon the great international variations observed for the common cancers and, particularly, upon migrant studies. In some instances we even have conclusive or promising evidence regarding the nature of some of these agents-the Epstein-Barr virus (Burkitt’s lymphoma and nasopharyngeal carcinoma), the hepatitis B virus (hepatocellular carcinoma), betel nuts (esophageal carcinoma), cigarette smoking (lung, bladder and some other cancers], and animal fat (colon and breast cancer). Yet we find that all of the major cancers occur in all countries and it, therefore, becomes unlikely that elimination of these environmental agents will eradicate cancer. There seems to be some “background” level of each cancer worldwide. Cancer can evidently occur in persons who have neither genetically nor environmentally imposed risk. We can, therefore, classify cancers broadly (Table I] with respect to their causation [6]. What is the mechanism that accounts for “background” cancers? If it is true that most environmental carcinogenesis is mediated via mutation in somatic cells, and if the dominantly heritable familial cancers are attributable to germinal mutations, then a natural hypothesis is that the background incidence of cancer is caused by “spontaneous” mutation in somatic cells. Spontaneous mutations are best known, and most readily demonstrated as mutations, when they occur in germ cells. But they also occur in somatic cells and are
2
July 1980
The American Journal of Medicine
Volume 69
widely regarded as playing a major role in carcinogenesis. Environmental mutagens/carcinogens can increase the rate at which somatic mutations occur. The genes that are mutated are probably the same in both the spontaneous and induced forms of a given cancer, although the molecular changes in DNA are sometimes different. Cancer will develop when a “cancer gene” is mutated in a cell that is able to express the mutation. These “cancer genes” may well be the same ones that have undergone mutation in germ cells to give rise to the dominantly inherited familial cancers; a specific cancer may result from mutation regardless of “cause,” and that mutation may be at the same genetic site in each instance. This is a hypothesis to be tested. A consequence of this hypothesis is that identification and characterization of the genes responsible for familial cancer would be at the same time an identification and characterization of the genes that are altered in “environmental” and “background” cancers. Anything learned about the correction of these gene defects might find application to all cancer. The genetic cancers would have an importance well beyond their incidence in the general population. Great progress has been made in the past few years towards the identification of human cancer genes, largely as the result of the powerful chromosomal banding techniques introduced early in the past decade. For two tumors, retinoblastoma and Wilms’ tumor, there are genetic forms in which a specific chromosomal deletion is present in every somatic cell; the defect is a visible germinal mutation [7,8]. The deletion imposes an exceedingly high risk for a site-specific tumor, just as occurs with the more usual dominantly heritable genes in which no chromosomal abnormality is apparent in normal somatic cells. A new cytogenetic technique introduced by Yunis and Ramsay [7] is capable of revealing subtle aberrations and will undoubtedly lead to the demonstration of more deletion cases that are not apparent with standard techniques. Cytogenetic analysis should also be able to verify the assertion that similar specific chromosomal aberrations are present only in tumor cells in nonhereditary cases and so substantiate the notion that a specific cancer can result from germinal or somatic mutation at a particular gene site
kc
Let us assume that some 100 to 200 cancer genes can be identified. They may have similar functions in that each is important for differentiation in a specific tissue.
EDITORIAL-KNUDSON
Ability to detect cells (lymphocytes or fibroblasts] that bear these genes could lead to the means for identifying persons at high risk; explication of the molecular defects associated with these mutations could advance our understanding of the fundamental defects in cancer cells and of the means for correcting them. For these reasons, familial cancer should continue to attract the attention of both physician and scientist.
REFERENCES 1. 2.
Cleaver JE, Bootsma D: Xeroderma pigmentosum. Annu Rev Genet 1975; 9: 19-38. Paterson MC, Smith PJ: Ataxia telangiectasia: an inherited human disorder involving hypersensitivity to ionizing ra-
diation and related DNA-damaging chemicals. Annu Rev Genet 1979; 13: 291-318. 3. Swift M, Sholman L, Perry M, et al.: Malignant neoplasms in the families of patients with ataxia-telangiectasia. Cancer Res 1976; 36: 209-215. 4. Kellermann G. Shaw CR, Luyten-Kellermann M: Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma. N Engl Med 1973; 289: 934-936. 5. Paigen B. Gurtoo HL, Minowada J. et al.: Questionable relation of aryl hydrocarbon hydroxylase to lung-cancer risk. N Engl J Med 1977: 297: 346-350. 6. Knudson AG: Genetics and etiology of human cancer. Adv Hum Genet 1977; 8: l-66. 7. Yunis JJ, Ramsay N: Retinoblastoma and subband deletion of chromosome 13. Am J Dis Child 1978; 132: 161-163. 8. Francke U, Holmes LB, Atkins L. et al.: Aniridia-Wilms’ tumor association: evidence for specific deletion of 11~13. Cytogenet Cell Genet 1979; 24: 183-192. 9. Knudson AG: Retinoblastoma: a prototypic hereditary neoplasm. Semin Oncol1978; 5: 57-60.
July 1666
The American Journal of Medicine
Volume 66
3