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MECHANISMS OF RADIATION-INDUCED CANCER 135 3 Mechanisms of Radiation-Induced Cancer BACKGROUND Carcinogenesis is viewed as a multistep process in which two or more intracellular events are required to transform a normal cell into a cancer cell. The concept that carcinogenesis involves more than one step is derived from three main lines of evidence: (1) the rate of mortality from cancer increases as a power function of age, (2) a long latent period typically intervenes between exposure to a known carcinogen and the appearance of cancer, and (3) three distinct and separate stages have been identified in experimental carcinogenesis: initiation, promotion, and progression. The fact that the cumulative incidence of cancer increases approximately as the seventh power of age during adult life prompted early investigators to postulate the existence of seven successive events, or steps, in the conversion of a normal cell into a cancer cell; these events, were thought to involve mutational changes in the broadest sense (Ar54). This concept failed to recognize, however, the high rates of somatic mutation that such a seven-stage model would require, the dynamic state of the target cells, and the peculiar age distributions typical for the cancers occurring during childhood. If the kinetics of target cells and the possible growth advantage of preneoplastic cells are taken into account, the age distributions of pediatric and adult cancers can be explained in terms of just two rate-limiting mutational steps (e.g., see Mo81), although other events that might be associated with tumor progression or tumor metastasis are not excluded. In a tumor that has grown to a population of 106 cells, even events that occur only rarely in each cell division can be expected to occur with a high
MECHANISMS OF RADIATION-INDUCED CANCER 136 probability in the total cell population. Models that account for all of the complex factors involved in the mechanisms of carcinogenesis have not yet been developed to the point where they can be used realistically for risk estimation, especially in view of the fact that the sparsity of data available makes it difficult to choose among the various possibilities. In Chapter 4 of this report, therefore, descriptive empirical models are used to arrive at cancer risk estimates. MECHANISMS The mechanisms by which radiation may produce carcinogenic changes are postulated to include the induction of: (1) mutations, including alterations in the structure of single genes or chromosomes; (2) changes in gene expression, without mutations; and (3) oncogenic viruses, which, in turn, may cause neoplasia. Although controversy persists as to the relative importance of these hypothetical mechanisms in the induction of carcinogenesis, they are not mutually exclusive, since different mechanisms may be involved at successive stages in carcinogenesis. The somatic mutation theory of carcinogenesis, proposed by Boveri in 1914 (Bo14), has received further support from the high correlation between the carcinogenicity and the mutagenicity of different agents. In a few types of cancer (e.g., retinoblastoma), moreover, the same specific gene mutation or deletion is found both in familial and nonfamilial cases, as noted in Chapter 1, suggesting that the mutation or the deletion of the gene plays a causative role, as discussed below. It is possible, on the other hand, that premalignant or malignant alterations do not necessarily result from changes in gene or chromosome structure per se, but from changes in gene expression. Support for this concept comes from evidence that nuclei transplanted from cancer cells into enucleated ova or blastocysts can produce apparently normal organisms or tissues in various species, including mice (Br77). Nevertheless, altered gene expression does not exclude the possibility that premalignant cells might undergo mutation during their conversion to cancer cells. Initiation, Promotion, and Progression in Carcinogenesis The following generalizations about the process of carcinogenesis are noteworthy: (1) The effects of radiation and chemical carcinogens which lead to cancer are dose dependent and generally irreversible; (2) the carcinogenic process is dependent on cell proliferation; (3) the changes that initiate carcinogenesis in a cell are passed on to daughter cells; (4) the subsequent events in carcinogenesis can be profoundly influenced by various noncarcinogenic factors; and (5) tumors tend to become increasingly
MECHANISMS OF RADIATION-INDUCED CANCER 137 malignant with time through the stepwise outgrowth of progressively more malignant subpopulations of tumor cells. It is now widely accepted that initiation, the first step in malignant cell transformation, begins the carcinogenic process, while in most cases promotion is required to complete the process (Co83). This concept of carcinogenesis as a two-stage process was suggested originally by studies of tumor induction in mouse skin in which a dose of chemical carcinogen that was too small to cause a detectable increase in the incidence of tumors was found to induce a high incidence of tumors if it was followed by repeated administration of a suitable promoting agent, an agent that did not cause tumors when administered alone (Bo74a, Be75). A synergistic interaction between the initiating effects of radiation (or various chemicals) and specific promoting agents is now known to occur in many different organs and cell systems (Mo64, Pe85, Ja86, Ke84a). In these studies, it was observed that promotion caused a higher incidence of cancer with a shortened latent period (Ry71). It has been widely assumed that a similar two-stage mechanism involving initiation and promotion exists for radiation carcinogenesis. Whereas most initiating agents, including radiation, are carcinogenic by themselves in a single exposure if they are administered in a sufficiently large dose, promoting agents must be given repeatedly over long periods of time, during which successive phases of promotion may be distinguishable (Pe85). Different promoting agents, moreover, may act at different stages of promotion. By the same token, different agents that inhibit promotion may act at different stages in the process (Pe85). The term tumor progression has been used traditionally to denote the acquisition of increasingly malignant properties within an established cancer, presumably via genetic instability. However, the term has also come to be used to denote the conversion of a benign growth into a malignant growth. In either case, the process reflects the proliferation of a subpopulation of cells within a tumor. This subpopulation of cells expands and overgrows the less aggressive cells. Radiation has been shown to be capable of enhancing the process of progression (Ja87). Other clastogenic agents such as hydroxyurea (Hah86) may also be progression agents for carcinogenesis (Personal Communication, Dr. Henry Pitot). Similarly, initiation-promotion-initiation experiments, in which promotion is followed by a second initiation step brought about by the administration of an initiator, have been found to increase the final incidence of malignant, as opposed to benign tumors (Mo81, He83). While initiation is thought by some investigators to result from mutational events, promotion appears to involve non-mutational effects on the kinetics of intermediate-stage cells. The first step in the initiation of carcinogenesis, whether by radiation or a chemical carcinogen, has been observed to be an event that occurs
MECHANISMS OF RADIATION-INDUCED CANCER 138 in a large percentage of treated cells (Ke85a, Cl86a, Cl86b, Wa88). The frequency with which this event can be produced experimentally far exceeds the frequency of mutations at any one gene locus, contradicting the notion that the initiating event is a specific single-locus mutation. Instead, initiation more likely appears to be an event that increases the genomic instability of the cells in subsequent rounds of cell division (Cl86b, Wa88, Ke84b). Although much experimental data has suggested that the first event in radiation and chemical carcinogenesis is a widespread, nonmutagenic type event, the same data has suggested that later events in the carcinogenic process appear to behave like mutations. Thus the notion that mutagenic events may occur in carcinogenesis still has widespread support, as indicated elsewhere in this report. The hypothesized high-frequency initiating event could conceivably be a change in gene expression (for example, see Fa80) of a type that might occur in a large proportion of irradiated cells (Sc85); in Escherichia coli, for example, radiation induces an error-prone DNA repair system (the SOS system) which leads to mutations that would otherwise occur only rarely (Wi76). Although the SOS system is activated for only a short period of time, other radiation-induced systems may be activated for longer periods; for example, recombinational events in yeast continue to occur for many generations after irradiation (Fa77). In this connection, it is noteworthy that SOS functions are also activated by a protease (Li80a) but are suppressed by protease inhibitors (Me77), which also suppress radiation-induced recombination in yeast (Wi84) and radiation- induced malignant cell transformation in vitro (Ke85b). Many other agents that enhance or suppress carcinogenesis in vivo exert similar effects on malignant cell transformation in vitro (Ke84a); these include retinoids (vitamin A derivatives), antiinflammatory steroidal agents, antioxidants, vitamins, protease inhibitors, and other substances (Sl80, Pe85, Wa85, Ke84a). After exposure to a carcinogen, proliferation of the exposed cells is essential to their subsequent neoplastic transformation. Tissue irritation, which stimulates cell division, was recognized long ago to increase the probability of tumor development; for example, following carcinogen treatment of the skin or liver, wounding of the skin or partial hepatectomy enhances tumor formation in the skin or liver, respectively (Su73). Similarly, the carcinogenic effects of 210Po alpha radiation on the lung of the hamster are enhanced by repeated instillation of saline into the airway, which stimulates proliferation of pulmonary epithelial cells (Li78, Sh82). Likewise, cigarette smoke, which contains small amounts of many known carcinogenic agents (such as 210Po) and which is a potent irritant, appears to potentiate the effects of inhaled radon and its daughter products in uranium miners (Lo44, Lu71, Sa84). Proliferation is thought to play a role in the fixation of radia
MECHANISMS OF RADIATION-INDUCED CANCER 139 tion damage which leads to malignant transformation in the expression of that damage and in the promotional phase of cancer development. The mechanism of tumor promotion is still obscure. Promoters such as phorbol esters are known to interrupt intercellular communication in some cell populations (Tr82), and they have traditionally been thought to be nonmutagenic (Ma83) and thus to act through effects on gene expression (Bo74). Recently, however, some such agents have been found to produce chromosome aberrations (Em81), aneuploidy (Pa81), sister chromatid exchanges (Ki78, Na79), and single-strand breaks in DNA (Bi82). Many promoting agents, moreover, induce free radicals in cells (Go81, Fi85). These free radicals can, in turn, damage DNA. It is noteworthy, therefore, that free radical-generating agents can act as tumor promoters (Ke86) and that inhibitors of free radical reactions can suppress tumor promotion in some systems (Sl83). Radiation itself also can enhance tumor promotion, tumor progression, and the conversion of benign growths to malignant growths (Ja87). To the extent that the effects of radiation are mediated by free radicals (Li77), which can also mediate the effects of promoting agents (Co83), sequential exposures to radiation may serve to promote tumorigenesis through mechanisms similar to those of chemical promoting agents. Natural hormones also may promote carcinogenesis in irradiated individuals. However, it is not yet clear how comparable the effects of hormones are compared to the effects of the classical promoting agents. Hormonal promotion conceivably may be mediated through physiological effects on the proliferation and differentiation of cells (Cl86a,b, Wa88). It may also be mediated through autocrine growth factors or their receptors, such as those that may be under the influence of certain oncogenes (Sp85). In some cases, hormones may actually suppress tumor promotion by inducing differentiation in cells that are at risk. Other factors capable of having a highly significant effect on the various stages of carcinogenesis include age, sex, genetic constitution, capacity to repair DNA, carcinogen metabolism, immunologic status, and dietary factors such as caloric intake (Su73). Radiobiological Factors Affecting Oncogenic Transformation During the past two decades, much information has been gathered about radiation carcinogenesis from experimental systems in which cultured mammalian cells are transformed to a malignant state by exposure to radiation. In vitro transformation assays have been used extensively to study the carcinogenic effects of radiation in a highly quantitative fashion and in a defined environment. One major advantage of such in vitro systems is
MECHANISMS OF RADIATION-INDUCED CANCER 140 that the effects of radiation on specific target cells can be studied directly without the presence of extraneous factors, which complicate carcinogenesis in vivo. In addition, transformation assays are extremely sensitive, allowing detection of the carcinogenic effects of radiation at doses below those at which statistically significant carcinogenic effects have been observed in animal and human studies. It has been observed by many investigators that radiation- induced transformation in vitro can be modified in the same way as radiation- induced cancer in animals, with the yields of malignant cells varying similarly in response to different characteristics of the radiation (such as total dose, dose rate, fractionation pattern, linear energy transfer (LET), etc.) and many other modifying factors, as described below. It is widely inferred that the processes involved in radiation-induced transformation in vitro are similar to those involved in carcinogenesis in vivo, and that results from in vitro studies are applicable to radiation-induced cancer in vivo. In vitro transformation systems also offer an approach to studying radiation carcinogenesis that is less expensive and less time-consuming than animal experiments. Dose Response Commonly used in vitro transformation assays can be divided into two broad classes. First, there is the use of short-term cultures of embryo cells, with clonal assays in which transformed clones can be identified after an incubation period of about 14 days. The transformation frequency and the surviving fraction can then be assessed from the same culture dishes. Second, there are assays with established cell lines (such as 3T3, 10T1/2, Rat 2) that have become immortal. These are focal assays, and for transformed foci to become identifiable, the culture must be continued for some weeks after the normal cells have reached confluence. Cell survival and transformation frequency cannot be assessed from the same culture dishes. Results can be expressed as transformation frequency per surviving cell, but because the transformation frequency observed is a function of the number of viable cells seeded per culture dish, the data can also be expressed in terms of the number of viable cells seeded per culture dish, the data can also be expressed in terms of the number of foci per dish or the fraction of culture dishes bearing foci. These in vitro assays, based on rodent fibroblasts, have been used widely because they are highly quantitative. Ideally, assays based on human epithelial cells would be more relevant, but, although transformation in human cells has been demonstrated as a result of exposure to radiation or chemicals, quantitative assays are not available. In recent years, in vivo transformation assays also have been developed for thyroid and mammary cells in rats. Cells are irradiated in situ in the thyroid or mammary gland and are subsequently excised and transplanted
MECHANISMS OF RADIATION-INDUCED CANCER 141 to a fat pad in a suitably prepared animal. Cell survival and transformation incidence can be determined in this way (C186a, C186b). Experiments using different initial cell densities or reseeded/diluted cell cultures have indicated that the malignant transformation of cells arises from very few carcinogen treated cells (Ke85a, C186b). These results have led to the notion that the first event in carcinogenesis is a high frequency event as discussed earlier. FIGURE 3-1 Probability of survival (top) and transformation per irradiated cell (bottom) as a function of dose (Ha80). The dose-response relationship for the induction of radiogenic transformation reflects a balance between an increase with dose in the proportion of cells that are transformed and a decrease in cell survival. This is illustrated in Figure 3-1 (Ha80). For gamma rays and other low-LET radiations, the cell survival curve is characterized by a broad initial shoulder
MECHANISMS OF RADIATION-INDUCED CANCER 142 region before it becomes steeper and approaches an exponential function of dose at higher doses (Figure 3-1) (Ha80). Transformation incidence, as expressed by frequency per surviving cell, increases with dose up to a few Gray, and reaches a plateau at higher doses. While the transformation data are often plotted in terms of frequency per surviving cell, they can also be expressed as frequency per initial cell at risk when applying these in vitro data to whole organisms. This approach is also illustrated in Figure 3-1 where the dose-response transformation curve rises at low doses, reaches a maximum, and falls at higher doses to eventually parallel the cell-killing curve. The curve represents a balance between transformation and cell killing and indicates that cells destined to become transformed have a survival response similar to that of untransformed normal cells. The peak of the dose-response curve for transformation frequency per initial cell at risk often reaches higher values for densely ionizing radiations, such as neutrons and alpha particles than for x rays or gamma rays. Dose Rate and Dose Fractionation For low-LET radiations, the consensus is that cell survival is enhanced by a decrease in the dose rate or separation of the dose into a number of fractions. Effects on the yield of transformants, however, are more complex. It has been reported that for low-LET radiations, splitting or fractionating the dose or reducing the dose rate can either enhance (Bo74, Ha81, Li79) or decrease (Hi84) the transformation frequencies in a variety of in vitro transformation models. More recent studies suggest that the proliferative status of the cells may account for some of the observed variation (Lu85). Using C3H10T1/2 cells, Hill et al. (Hi85) have compared dose-response transformation curves for gamma rays and for fission spectrum neutrons delivered in both a single exposure or in multiple small fractions. Although fractionation was observed to result in a sparing effect on transformation by gamma rays, it increased the rate of transformation by fission spectrum neutrons (Ha79, Hi85). Since enhanced transformation was observed after exposure to multiple low doses or a continuous low dose rate, compared to high-dose-rate fission spectrum neutrons, the relative biological effectiveness (RBE) of neutrons relative to that of gamma rays was larger at low-dose rates than at high-dose rates. As outlined in chapter 1, these observations have important practical implications for the selection of an appropriate RBE for neutrons. Linear Energy Transfer (LET) Comparisons of various high-and low-LET ionizing radiations for their abilities to induce oncogenic transformation in several cell systems
MECHANISMS OF RADIATION-INDUCED CANCER 143 have been reported. In general, high-LET radiations are far more cytotoxic and oncogenic than low-LET radiations such as x rays or gamma rays. Furthermore, the RBE for oncogenic transformation and cytotoxicity increases with increasing LET of the radiation. Hence, if the transformation frequencies for each type of high-LET particle are plotted against the corresponding survival values, the curves obtained cannot be superimposed. This suggests that there is a real difference in the RBE between cell killing and transformation (He88, Ya85) and also indicates that there is a significant frequency of transformation at doses of high-LET radiations that have very little effect on cell survival. Figure 3-2 (Ha87a) shows survival and transformation data for gamma rays and high-LET helium-3 ions. The cell survival curve for gamma rays has a broad initial shoulder, while that for helium-3 ions is an exponential function of dose. For high-LET particles, the transformation frequency peaks at a much lower dose than for gamma rays and reaches a value that is higher by a factor of about 5 than is the case for gamma rays (Ha87a). Neutrons are also highly effective at inducing transformation. Figure 3-3 shows the variation of RBE with neutron energy over a wide range, FIGURE 3-2 Cell survival curves and dose response relationships for oncogenic transformation for C3H10T1/2 cells irradiated with either gamma rays or high- LET helium-3 ions. Transformation frequencies are expressed in two ways; per surviving cell and per cell initially at risk (Ha87a).
MECHANISMS OF RADIATION-INDUCED CANCER 144 which is similar to that received by individuals during the bombing of Hiroshima (Mi89). Energies of about 350 kiloelectron volts (keV) are most effective for both cell lethality and transformation. There is evidence that the effectiveness of neutrons increases with a decrease in the dose rate. As a consequence of this, RBE values are higher for a fractionated or a low-dose-rate exposure, than for a single, brief exposure, as mentioned above. It has been suggested that the misrepair of sublethal radiation damage in fission neutron- irradiated cells may account for the increased RBE values (Hi85). FIGURE 3-3 RBEm for cell curvinal and for oncogenic transformation as a function of neutron energy and C3H10T1/2 cells irradiated with monoenergetic neutrons (Mi89). Alpha Particles The transforming ability of alpha particles also has been studied extensively with in vitro transformation systems. Robertson et al. (Ro83) showed that the RBE for transformation by plutonium-238 alpha particles in Balb/3T3 cells was substantially higher than that for cell lethality. It was also demonstrated that potentially lethal damage was repaired in x-irradiated 3T3 cells and was not repaired in alpha-particle irradiated cells, resulting in a high RBE value for oncogenic transformation in alpha-irradiated plateau-phase cultures. Similar findings have also been reported by Hall and Hei who used
MECHANISMS OF RADIATION-INDUCED CANCER 145 the C3H10T1/2 cell system (Ha85). At equivalent doses, alpha particles were substantially more cytotoxic than gamma rays and were more efficient in inducing oncogenic transformation. The calculated RBE value for alpha particles ranged from 2.3 to 9 over the range of doses studied, with the highest RBE value at the lowest dose. Recent results have suggested the absence of a dose-rate effect with alpha particles (Hi87). Previous studies by Lloyd et al. (Ll79) showed that at a dose corresponding to a surviving fraction of 37%, about 14 particles traversed the nucleus for each cell killed. The fact that on the average 13 particles may traverse a cell nucleus without killing the cell may explain the high efficiency with which high-LET particles induce transformed loci. Agents that Modify Radiation Transformation Many different classes of agents have been shown to modify radiation- induced transformation in vitro (Ke84a). The tumor promoting agent 12-O- tetradecanoyl phorbol acetate (TPA) has been studied in many laboratories for its ability to enhance radiation-induced transformation. It is of particular interest that promoting agents such as TPA can change the shape of the dose-response curve for radiation-induced transformation, making it linear (Figure 3-4) (Ke78). This alteration of the dose-response relationship also occurs in promotion by TPA of radiation carcinogenesis in vivo (Figure 3-5) (Fr84). While promotion can greatly enhance radiation transformation, other agents can suppress radiation transformation or the enhancement by TPA (Ke88). An example of the suppressive effect of the protease inhibitor antipain on radiation transformation and the TPA enhancement of radiation transformation is shown in Figure 3-6. Other examples of agents which suppress radiation transformation are selenium (Figure 3-7), which is thought to exert its inhibitory action by inducing glutathione peroxidases, and 5-aminobenzamide, which is an inhibitor of poly-ADP-ribose synthetase. The frequency of transformation resulting from a given dose of radiation can also be modulated by the level of thyroid hormone in the serum. With high levels of T3 hormone (corresponding to hyperthyroid conditions) the transformation incidence resulting from 3 Gray of x rays is increased, while with low levels of T3 hormone, (corresponding to hypothyroid conditions), the transformation incidence is not detectable above the spontaneous level. The suppressing effects of some of these agents are illustrated in Figure 3-7 (Ha87a). GENETICS OF CANCER As noted above, much evidence supports the concept that mutation is involved in the etiology of cancer. Recent research has identified critical
MECHANISMS OF RADIATION-INDUCED CANCER 146 FIGURE 3-4 Dose-response curve for the induction of radiation transformation, with or without enhancement by TPA. Note how a promoter changes a linear quadratic response to a linear one (Ke78). FIGURE 3-5 U.V. light-induced skin cancer, with and without promotion by TPA (Fr84).
MECHANISMS OF RADIATION-INDUCED CANCER 147 genes that are thought to be the sites of oncogenic somatic mutations. Over the past decade, research on the mechanisms of carcinogenesis has focused on such genes, of which two broad classes are now known to exist: (1) protooncogenes and (2)tumor-suppressor genes, or antioncogenes (Kn85). FIGURE 3-6 Suppressive effect of a protease inhibitor (antipain) on radiation transformation in vitro, both with and without promotion by TPA (Ke88). Protooncogenes Protooncogenes, which may give rise to oncogenes, seem to be important in the origin of at least some forms of human cancer. The list of such genes has grown apace with new means for identifying them. Alterations of the ras protooncogene have now been observed in several different types of radiation- induced tumors, including murine lymphomas (Gu84a, b), plutonium-induced malignancies (Fr86b), and radiation-induced rat skin tumors (Sa87, Ga88, Ga86). Radiation has also been shown to activate other oncogenes presumed to be involved in carcinogenesis, including c-myc (Sa87, Ga86, Ga88) and oncogenes that are not members of the ras
MECHANISMS OF RADIATION-INDUCED CANCER 148 gene family but which cause transformation in the NIH 3T3 cell transfection assay system (Bo87, Ja88). The activation of myc has been shown to occur by amplification, translocation, and internal rearrangements. FIGURE 3-7 Effects of vitamin A analogues, selenium, vitamin E, 3-amino-benzamide, and TPA, at 4 Gy and T3 (thyroid hormone) at 3 Gy on radiation transformation (Ha87a). Although there is evidence for some specificity in the pattern of oncogene alterations that is produced by a given carcinogen, it is still not possible on the basis of an oncogene ''signature" to determine the cause of a given tumor, that is, whether the tumor was caused by radiation or some other carcinogen. The stage at which a given oncogene is activated in the carcinogenic process also remains to be determined. While in some instances activation may occur as a late step in carcinogenesis (Su83, Su84, Ru84), evidence implies that in other instances it may occur early (Ba87, Ba87b). It is note-worthy that protooncogene loci are involved in the specific chromosomal changes that are associated with certain types of cancer (Ha87a, Ro84). This implies that such alterations of protooncogene structure or function play a causal role in the occurrence of those types of cancer. It is not known, however, whether the changes are early or late events in the origin of the neoplasms (Li80a, Fi81).
MECHANISMS OF RADIATION-INDUCED CANCER 149 Some oncogene alterations clearly represent steps in tumor progression. An example is the amplification of the myc family of oncogenes in neuroblastomas and in small-cell carcinomas of the lung (Br84, Na86). This amplification is often cytogenetically evident in the form of double minute chromosomes consisting of repeated chromosomal pieces, including the oncogene in question. In these instances amplification signifies an advanced stage of disease and carries a poor prognosis. A role for oncogenes in the earliest stage of oncogenic transformation could be better supported if individuals who carried such mutations in their germ lines were found. This has not been found as yet in humans, but susceptible mice have been produced experimentally by transgenically introducing an activated oncogene into the germ line. Mice with a strong predisposition for the development of lymphoma or mammary cancer have resulted from the introduction of a c-myc gene, fused with an immunoglobulin enhancer, or with the strong long terminal repeat (LTR) promoter of the mammary tumor virus, respectively (Ad85, St84). The tumors are clonally distinct, however, indicating that at least one somatic event occurred subsequently in their development. This finding parallels results of in vitro experiments showing a requirement for the activation of at least two different oncogenes in the transformation of normal rat embryo cells (La83a,b). Tumor-Suppressor Genes (Antioncogenes) The second class of cancer genes that has been identified was discovered through studies of individuals with inherited predispositions for specific cancers. For many cancers including carcinomas of colon, breast, lung, stomach, ovary, uterus, kidney and bladder, glioma, melanoma, leukemias, and lymphomas there is a subgroup of persons at higher than normal risk by virtue of the fact that they have inherited a specific mutation. This type of predisposition is transmitted in a Mendelian dominant fashion, although the different underlying mutations vary in their penetrances. Well-known examples of such predisposing conditions are familial polyposis coli (chromosome 5, Wilms' tumor (chromosome 11), and the hereditary form of retinoblastoma (chromosome 13). The latter tumor has been the prototype in research on this group of genes (Kn85). About 40% of the individuals with retinoblastoma carry germ-line mutations that predispose them to the disease. The offspring of such persons have a 50% risk of developing the tumor. About 30% of the individuals with retinoblastoma have bilateral disease; all of the latter carry the germ-line mutation. A small fraction of cases (3-5%) bear a constitutional deletion in chromosome 13, a finding that has facilitated the
MECHANISMS OF RADIATION-INDUCED CANCER 150 search for the responsible gene. Genetic linkage studies have shown that the heritable cases without a deletion involve a mutation at the same site. Although carriers of the mutation develop a mean of three to four tumors, the inherited mutation alone is not sufficient for the production of the cancer; another event is necessary. The second event that is necessary is the loss or mutation of the normal allele on the other chromosome 13 by nondisjunction, deletion, genetic recombination, or local mutation (Ca82, Kn85). The result in all cases is the same: the tumor cell contains no normal copy of the retinoblastoma gene. Hence, although inheritance of the predisposition is dominant, oncogenesis at the cellular level is recessive. Therefore, the normal allele can be viewed as protective, thus, the designation tumor-suppressor gene, or antioncogene. Patients with retinoblastoma have a high risk of developing osteosarcoma of the orbit following radiation therapy. They also have a lesser predisposition to osteosarcoma in the absence of irradiation. In either case, the genetic change in the tumor cells is the loss of the two normal alleles of the retinoblastoma gene; thus, this gene is a tumor-suppressor gene for osteosarcoma (Ha85) as well as for retinoblastoma. The probability of mutation or loss of the normal gene in persons born with one mutant gene in the germ line is apparently increased by radiation, as would be expected. The retinoblastoma gene has recently been cloned, an accomplishment that will greatly facilitate investigation of the relevant oncogenic mechanism, the identification of those at risk, and the study of the physiology of the gene in normal development (Fr86a, Fu87b, Le87a, Le87b). It has already been shown that the messenger RNA (mRNA) of the gene is absent or defective in virtually every case of retinoblastoma, whether it was inherited or not. In the nonhereditary cases, the two normal genes are lost or mutated as the result of two somatic events, the second events being of the same kinds as those observed in heritable cases (see above). The only difference between the two forms of tumor is that the first event is present in the germ line in one form and occurs after conception in the other. The idea that recessive genes may suppress the oncogenic process is not new. Previous experiments with somatic cell hybrids have shown that the neoplastic character of most tumor cells can be suppressed by fusing the cells with normal cell partners (St76). On the other hand, it is clear that oncogenes are frequently abnormal in structure and/or function in many tumors. It is probable, therefore, that protooncogenes and tumor-suppressor genes are both important in carcinogenesis. Whether either or both are necessary in every case of cancer remains to be determined. Recessive Breakage and Repair Disorders These disorders, which include xeroderma pigmentosum, ataxia telangiectasia, Fanconi's anemia, and Bloom's syndrome, are recessively inherited
MECHANISMS OF RADIATION-INDUCED CANCER 151 conditions that predispose the chromosomes of an individual to breakage and/or defective repair of DNA damage (Han86). They do not involve cancer genes of the types discussed above but can be viewed as conditions that increase the probability of a cancer-producing mutation. Thus, in xeroderma pigmentosum a defect in excision repair permits an increased rate of mutations at all genetic loci in cells exposed to sunlight. Ataxia telangiectasia predisposes the chromosome to breakage, especially in lymphocytes; the underlying molecular defect is not known, but it is thought to involve a defect in DNA repair. Patients with the syndrome are especially predisposed to lymphoid neoplasia, and their cells are highly sensitive to ionizing radiation. Chromosome breakage and rearrangement are regular features of Fanconi's anemia, which predisposes an individual to acute myelomonocytic leukemia; the underlying molecular defect for this is not known. Finally, Bloom's syndrome is associated with high rates of mutation and of sister chromatid, and even homologous chromosome, exchanges. The molecular defect apparently involves a ligase that is important in the repair of DNA damage (Ch87, Wi87). The syndrome predisposes an individual to several kinds of neoplasia, perhaps by facilitating mutation, somatic recombination, and the expression of recessive oncogenes. Genetic Polymorphism for Metabolism of Carcinogens In contrast to the aforementioned DNA repair disorders, in which the response to an environmental agent is altered, there are cases in which the response may be normal but the amount of radiant energy imparted is increased. Thus, albinos are sensitive to ultraviolet light because they absorb more of it, not because they have a defective DNA repair mechanism. Such a genetic predisposition is also known for many chemical carcinogens (Ca82, Ko82, Ay84, Go86). Hence, to the extent that the effects of a given chemical may promote the carcinogenic effects of radiation, traits affecting the metabolism of the chemical may alter susceptibility to radiation carcinogenesis. Hereditary Fragile Sites Another kind of inherited mutation that may predispose an individual to cancer is the hereditarily fragile genetic site. About 18 such sites are known. Fragility for a specific site can be elicited in vitro, and the fragility is transmitted in a Mendelian dominant fashion (He84). Although several of the sites have been found to be situated at or near break points that are known to be involved in various cancer-associated translocations (Le84), cancer does not appear to be common in families with such abnormalities.
MECHANISMS OF RADIATION-INDUCED CANCER 152 The importance of these mutations in carcinogenesis thus remains to be determined. EFFECTS OF AGE, SEX, SMOKING, AND OTHER SUSCEPTIBILITY FACTORS As discussed in the preceding section, the carcinogenic process includes the successive stages of initiation and promotion. The latter phase, promotion, appears to be particularly susceptible to modulation, with cigarette smoking being a conspicuous example of a modulating factor. Susceptibility to the carcinogenic effects of radiation can thus be affected by a number of factors, such as genetic constitution, sex, age at initiation, physiological state, smoking habits, drugs, and various other physical and chemical agents (UN82). The mechanisms through which these factors influence susceptibility are, however, not well understood. Moreover, they depend on the particular type of cancer, the tissue at risk, and the specific modifying factor under consideration. Therefore, the Committee elected to discuss the factors affecting carcinogenesis at specific organ sites in Chapters 4 and 5. Some general conclusions can be drawn from the observations reported in Chapter 4. Cancer rates are highly age dependent and, in general, increase rapidly in old age. The expression of radiogenic cancers varies with age in a similar way, so that the age-dependent increase in the excess risk of radiogenic cancer is conveniently expressed in terms of relative risk; that is, the increased risk tends to be proportional to the baseline risk in the same age interval. In some cases, however, such as breast cancer, the change in the baseline cancer rate with age is more complicated and possibly related to variations in hormonal status with age. Susceptibility to radiation-induced breast cancer may be similarly complicated, as outlined in Chapter 5, and there is some indication that protective factors for breast cancer in nonirradiated women, such as early age at the birth of the first child, may also be relevant for radiation-induced breast cancer. The situation is less clear for the risk factors for lung cancer. The BEIR IV Committee found that smoking and prolonged exposure to inhaled alpha- particle emitters interacted in a multiplicative fashion, or nearly so, with the result that the increased risk of radiogenic lung cancer in those of a given smoking status was proportional to the baseline risk for the same smoking status (NRC88); however, this may not be the case for acute exposures to x rays and gamma rays. It is commonly believed that the data on lung cancer and smoking among the atomic-bomb survivors support an additive risk model, in which there is no interaction between radiation and tobacco use. Nevertheless, the BEIR IV Committee's analyses of these
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