Chemical and Physical Carcinogenesis: Advances and Perspectives for the 1990S1

Home , Carcinogenesis

[CANCER RESEARCH (SUPPL.) 51, 5023s-5044s, September 15. 1991] Chemical and Physical Carcinogenesis: Advances and Perspectives for the 1990s1

Curtis C. Harris2

Laboratory of Human Carcinogenesis, National Cancer Institute, N1H, Bethesda, Maryland 20892

Abstract the initiated cells with both an altered responsiveness to their microenvironment and moreover exerts a selective clonal ex Carcinogenesis is a multistage process driven by carcinogen-induced pansion advantage when compared to the surrounding normal genetic and epigenetic damage in susceptible cells that gain a selective cells (26-28). The initiated cells may have decreased respon growth advantage and undergo clonal expansion as the result of activation siveness to the inter- and intracellular signals that maintain of protooncogenes and/or inactivation of tumor suppressor genes. There fore, the mutational spectra of chemical and physical carcinogens in these normal tissue architecture and regulate the homeostatic growth critical genes are of interest to define endogenous and exogenous muta and maturation of cells. For example, initiated cells may be less tional mechanisms. The p53 tumor suppressor gene is ideally suited for responsive to negative growth factors, inducers of terminal cell analysis of the mutational spectrum. Such an analysis has revealed differentiation and/or programmed cell death (4, 26, 29-35). evidence for both exogenous and endogenous molecular mechanisms of Perturbation of the normal microenvironment by (a) physical Carcinogenesis. For example, an informative p53 mutational spectrum of means, e.g., wounding of the mouse skin or partial hepatectomy frequent Gâ€”Â»Ttransversions in codon 249 is found in hepatocellular carcinomas from either Qidong, People's Republic of China, or southern in rodents, (b) chemical agents, e.g., exposure of the mouse skin to certain phorbol esters or exposure of the rat liver to Africa. This observation links exposure to aflatoxin B,, a known cancer risk factor in these geographic regions, with a specific mutation in a phÃ©nobarbital,(c) the inflammatory process, or (d) microbial cancer-related gene. Other studies indicate that abnormalities in genes agents, e.g., influenza virus enhancement of rodent lung carci- controlling the cell cycle may cause genomic instability and increase the nogenesis or hepatitis viruses in human liver Carcinogenesis, probability of neoplastic transformation. Finally, mechanistic understand may also foster such selective clonal expansion of the initiated ing of Carcinogenesis is leading to improved cancer risk assessment and cells (4, 17, 36, 37). to the identification of individuals at high cancer risk. Tumor promotion results in proliferation and/or survival of the initiated cells to a greater extent than normal cells and Introduction enhances the probability of additional genetic damage including endogenous mutations accumulating in the expanding popula Carcinogenesis is a mature multidisciplinary field of cancer tion of these cells. The probability of a subpopulation of initi research that has a rich history of scientific accomplishments ated cells converting to malignancy can be substantially in achieved by epidemiolÃ³gica! observations (1-3); development creased by their further exposure to DNA-damaging agents and exploitation of both animal models relevant to human (38-40) that may activate protooncogenes (41) and/or inacti cancer (4) and in vitro cell and tissue models including the use vate tumor suppressor genes. Malignant cells continue to ex of human tissues (5, 6); and most recently, advances in molec hibit progressive phenotypic changes during tumor progression ular genetics (7-II).3 Examples of conceptual advances and (42) and may exhibit intrinsic genomic instability that is man seminal observations in the areas of chemical and physical ifested by the abnormal number and structure of chromosomes, Carcinogenesis are listed in Table 1; advances in viral Carcino gene amplification, and altered gene expression (43-45). genesis are reviewed by Howley in this issue (12). This classical view of two stage Carcinogenesis involving a Since the research accomplishments of Carcinogenesis have mutation, tumor initiation, and an epigenetic change, tumor been extensively reviewed (13-25), this commentary will focus promotion, has been conceptually important but is also consid on selected topics that are especially relevant to current under ered to be simplistic in that the number of independent genetic standing of human Carcinogenesis and, in particular, to the and epigenetic events may be 6 or more in certain types of molecular epidemiology of human cancer, an emerging field in cancer (46-48). Furthermore, chemical carcinogens may: (a) cancer research. not be considered mutagens, termed nongenotoxic carcinogens (49); (b) have both genetic and epigenetic effects such as the Multistage Carcinogenesis ability to induce mutations and the property of decreasing DNA methylation, respectively (50) or increase cellular proliferation; Carcinogenesis is a multistage process driven by carcinogen- and (c) have a linear or non-linear dose-response relationship induced genetic and epigenetic damage in susceptible cells that with respect to tumor formation (51, 52). These and other gain a selective growth advantage and undergo clonal expansion observations have generated an active debate concerning both as the result of activation of protooncogenes and/or inactivation the contribution of endogenous mutagenic mechanisms, e.g., of tumor suppressor genes. The traditional view of carcinogen- oxy-radical DNA damage, DNA depurination, DNA polymer- esis (Fig. 1) is derived primarily from studies of animal models. ase infidelity, and deamination of 5-methylcytosine, versus ex The first stage of the carcinogenic process, tumor initiation, ogenous environmental mutagens and the value of animal bioas- involves exposure of normal cells to chemical, physical, or says to identify carcinogens and to aid in human cancer risk microbial carcinogens that cause a genetic change(s) providing assessment (53-63). This debate is not merely an academic one 1Presented at the Symposium "Discoveries and Opportunities in Cancer in that societal and regulatory decisions critical to public health Research: A Celebration of the 50th Anniversary of the Journal Cancer Research." are at issue. May 15, 1991, during the 82nd Annual Meeting of the American Association for Cancer Research, Houston, TX. 2To whom requests for reprints should be addressed, at Laboratory of Human Carcinogen Metabolism and DNA Damage Carcinogenesis, National Cancer Institute, N1H, Building 37, Room 2C05, Be thesda, MD 20892. 3 Due to space limitations and the breadth of this topic, comprehensive reviews Many chemical carcinogens require metabolic activation gen will be frequently cited and are the source of additional citations. erally to high energy electrophiles to exert their carcinogenic 5023s

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1991 American Association for Cancer Research. CARCINOGENESIS Table 1 Examples of advances in chemical and physical carcinogenesis" A. Cancer etiology I. Life-style factors (tobacco snuff or smoke) can cause human cancer. Hill. 1759(329) Soemmerring, 1795 (330) Doll and Hill. 1950(331) Wynder and Graham, 1950(332)

2. Occupational agents and factors can cause human cancer. a. Nun (childlessness) Ramazzini. 1713(333) b. Coal soot Pott, 1775(334) c. Sunlight Thiersch, 1875(335) d. Aromatic amines Rehn. 1895(337) e. Benzene DeLore and Borgman, 1928 (340) f. Ionizing irradiation Harting and Hesse, 1879 (336) Trieben, 1902 (338) Clune!, 1910(339) Martland and Humphries, 1929 (341) g. Asbestos Ministry of Labour and National Serv ice, 1949(342) Wagner et al., 1960(343)

3. Mixtures of chemicals (coal tar) can cause cancer in experimental animals. Yamagiwa and Ichikawa. 1918 (344)

4. Specific chemicals, e.g., dibenzanthracene or 2-naphthylamine, are carcinogens in experi Kennaway and Hieger, 1930 (345) mental animals. Hueper et al.. 1938(346) 5. Solid "inert" substances such as plastic can cause cancer when implanted s.c. in experimen Turner. 1941 (347) tal animals.

6. Naturally occurring compounds isolated from plants, e.g., croton oil, or marine organisms, Berenblum, 1941 (348) e.g.. teleocidin B and okadaic acid, have cocarcinogenic and/or tumor-promoting activities in Fujiki et al.. 1979(349) experimental animals.

7. Naturally occurring chemicals such as alkaloids from plants, Â¡-.K--brackenfern (Pleritlium Cook el al., 1950(355) aquilinum). cycad. and Senecio, and fungal toxins, e.g.. aflatoxin B,. can be carcinogens in Schoentalf/a/.. 1954(356) experimental animals. Laquer, 1964(357) Evans and Mason, 1965 (358) Carnaghan, 1965(359) Wogan, 1966(360) Wogan and Newberne. 1967 (361)

8. yV-Nitrosamines can be carcinogenic in laboratory animals. Magee and Barnes. 1956 (362)

9. Cooking of red meat, fish, or specific amino acids can generate polynuclear aromatic hydro Kuratsume, 1956(363) carbons and, in some cases, heterocyclic amines that are carcinogenic in animal models. Lijinsky and Shubik, 1964 (364) Sugimura et al.. 1977(365) Kasai el al.. 1980(366)

10. Tobacco smoking and alcoholic beverages are human cancer risk factors and have multiplic Wynder el al.. 1957(367) ative effects. Keller. 1967(368) Rothman and Keller, 1972 (369)

11. Exposure of the human fetus to ionizing radiation increases risk of leukemia. Stewart Ã©tal.,1958(370)

12. Tobacco smoking and occupational exposure to asbestos increases risk of human broncho- Selikofff/a/., 1968(371) genie carcinoma.

13. Dietary exposure to aflatoxin B, correlates with prevalence of human hepatocellular carci Alpert et al.. 1968(372) noma in Africa.

14. Animal bioassays can identify chemical carcinogens, e.g., chloromethyl ethers and vinyl Van Duuren el al.. 1968 (373) chloride, prior to epidemiological evidence. Viola el al., I97I (374)

15. Carcinogen-macromolecular adducts can be used as molecular dosimeters including exposure Ehrenberg el al.. 1974(296) to life-style and occupational carcinogens. Tornqvist et al.. 1986 (298) Farmer elal.. 1986(300)

16. Transplacental exposure to diethylstilbestrol increases risk of human vaginal carcinoma. Herbst et al., 1977(375)

17. Fiber dimension and length is correlated with carcinogenicity in animal models Stanton el al., 1981 (376) B. Multistage carcinogenesis 1. Chemicals can cause cancer at sites distant from the point of application in experimental Sasaki and Yoshida. 1935 (377) animals.

2. Metabolites of chemical carcinogens are predicted to be the active carcinogenic agent. Boyland. 1935(378)

3. Carcinogenesis is a multifactorial process involving tumor initiation and promotion in ani Rousand Kidd. 1941 (379) mal models. Berenblum. 1941 (348) Mottram. 1944(380) Berenblum and Shubik. 1949 (381)

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Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1991 American Association for Cancer Research. Table 1 Continued 4. Metabolic activation of some chemical carcinogens is essential for their carcinogenic activity. Millerand Miller. 1947(382) Miller et al., 1964(383)

5. Tumor promoters can inhibit cell-cell communication of mammalian cells in vitro. Murray and Fitzgerald, 1979 (384) \ott\etal., 1979(385)

6. A tumor promoter in experimental animals can specifically bind and activate a specific Driedgerand Blumberg, 1980 (386) cellular receptor. Castagna et a!., 1982 (387)

7. Oncogenes cooperate in neoplastic transformation of primary rodent cells. Land et al., 1983(388) Ruley, 1983(389)

8. Some tumor promoters act via the protein kinase C pathway for signal transduction. Davis and Czech. 1985 (390) Arroleo and Weinstein. 1985 (391) Ebeling et al., 1985(392)

9. Cooperation between oncogenes is demonstrated in transgenic animal models. Sinn Ã©tal.,1987(153)

10. Overexpression of protein kinase C leads to morphological transformation of rodent cells. Housey et al., 1988(393) Personsera/., 1988(394)

11. Multiple genetic events in protooncogenes and tumor suppressor genes are associated with Volgelsteinera/., 1988(395) human carcinogenesis. C. Genetic and epigenetic mechanisms of carcinogenesis 1. Human cancer can be inherited. Watkins, 1904(396)

2. Chromosomal abnormalities are predicted to be involved in cancer. Boveri, 1914(397)

3. Carcinogenic X-rays are also mutagens. Muller. 1927(398)

4. Inbred mouse strains differ in their cancer incidence. Forth et al., 1933(399) Strong, 1935(400)

5. Cancer may arise by inactivation of both alÃelesofa tumor suppressor gene. Charles and Luce-Clausen, 1942 (401) Knudson, 1971 (95) Comings, 1973(402) CaveneeÂ«a/.. 1983(96)

6. Chemical carcinogens can be mutagens. Auerbach et al., 1947 (403) Boyland and Horning, 1949 (404)

7. Chemical carcinogens may bind to DNA. Boyland, 1952(405) Wheeler and Skipper. 1957 (406) Brookes and Lawley. 1960 (407) Farber and Magee. 1960 (408)

8. A specific chromosomal abnormality can be associated with human leukemia. Nowell and Hungerford. 1960 (409)

9. UV light causes a specific type of DNA damage, i.e., thymidine dimers (cyclobutane). Beukers and Berends, 1960 (410)

10. Carcinogenic potency of some chemical carcinogens correlates with their binding level to Brooks and Lawley, 1964 (411) DNA in experimental animals.

11. Defective DNA repair may predispose to UV-induced human skin cancer. Cleaver, 1968(412)

12. Interindividual variation is observed in carcinogen metabolism and/or formation of carcino- Kuntzman et al., 1968 (413) gen-DNA adducts in human cells and tissues. Welch et al., 1968(414) Huberman and Sachs, 1973 (71) Harrisera/., 1976(415)

13. Normal cells are dominant in normal-tumor murine cell hybrids. Harris et al.. 1969(416)

14. In vitro bacterial mutagenesis can be used to screen putative carcinogens. Ã•mese/a/., 1973(417) McCann ff a/., 1975(418)

15. RNA viral oncogenes have a normal cellular counterpart (protooncogene). Stehelin et al., 1976(419)

16. Data consistent with the autocrine growth factor theory are presented. DeLarco and Todaro. 1978 (420)

17. DNA from chemically transformed rodent cells contain an oncogene(s). Shihetal., 1979(421)

18. Specific chromosomal loss is associated with tumorigenic revenants of normal-carcinoma Stanbridge et al., 1981 (422) human cell hybrids.

19. Chromosomal translocation can activate protooncogenes in human cells. Dalia-Pavera et al., 1982(423) deKlein et al., 1982(424) Shen-Ong et al.. 1982 (425) TaubÂ« al.. 1982(426)

20. Oncogenes are cloned from human cancers. Goldfarb et al., 1982(427) Pulciani et al.. 1982(428) ShÃ¬hetal.. 1982(429)

21. raj oncogene contains a base substitution when compared to protooncogene. Ready et al., 1982(430) Takinera/., 1982 (431) Taparowsky et al., 1982(432)

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Table 1 Continued 22. Chemical carcinogens can activate ras protooncogenes in animal models. Balmain and Pragnell. 1983 (433) Sukumar et al., 1983 (434)

23. Some mutant growth factor receptors are oncogenes in rodent cells. Downward et al., 1984 (435)

24. Site-specific mutagenesis analysis of carcinogen-DNA adducts confirms predications of nu- Loechler et al.. 1984(116) cleotide misincorporation opposite specific adducts. Preston et al.. 1986(436)

25. Transferred oncogenes can cause neoplastic transformation of human epithelial cells. Yoakum et al., 1985(437) Kliim Â«-iÂ«/..1985(438)

26. The human rctinoblastoma susceptibility (Kin gene is cloned. Friend et al., 1986(439)

27. Nuclear oncogenes can act as transcription factors. Makiera/., 1987(440) Vogtefa/., 1987(441) HÃ¶hnumn et al., 1987 (442)

28. Direct evidence of the tumor suppressor activity of the Rb gene in human cells. Huang Ã©tal..1988(147)

29. pS3 is frequently mutated in diverse types of human cancers. Baker et al., 1989(443) Nigroero/., 1989(127) Takahashi et al.. 1989(128)

30. p53 functions as a tumor suppressor gene in rodent and human cells. Eliyahu et al., 1989(444) Finlay Â«a/.. 1989(445) Baker et al., 1989(443)

31. A candidate tumor suppressor gene on chromosome 18q may be involved in human colon Fearonera/., 1990(446) carcinogenesis

32. NF1. a GTPase-activating protein, may be a negative regulator of ras p2l and a tumor Cawthon et al., 1990 (447) suppressor gene Xuetal., 1990(448) Wallace Ã©tal..1990(449)

33. A candidate Wilm's tumor suppressor gene is cloned. Callera/.. 1990(450) Gessler, 1990(451) 34. Germline />.\Ã¬mutationsare found in certain cancer-prone families. M:ilkiii <â€¢/Â«/..1990(141) Srivastavaera/., 1990(142) 35. Candidate tumor suppressor genes (MCC and APC) may be involved in familial adenoma- Kinzler et al., 1991 (452) tous polyposis and colorectal carcinoma. Kinzler et al., 1991 (453) Nishisho et al., 1991 (454) Graden et al., 1991 (455)

36. An environmental chemical carcinogen (aflatoxin B,) is linked with a specific mutation in Hsufia/., 1991 (137) the p53 tumor suppressor gene in human hepatocellular carcinogenesis. Bressac et al.. 1991 (138)

37. A candidate tumor suppressor gene (protein tyrosine phosphatase -y)on chromosome 3p LaForgia et al., 1991 (456) may be involved in human lung and renal carcinogenesis. Â°These historical reviews have been useful references and are a source of additional examples of advances in carcinogenesis (350-354).

Initiation Promotion Conversion Progression

â€¢Defectsin Terminal Differentiation â€¢Defectsin Growth Control â€¢Resistanceto Cytotoxicity

Fig. I. Carcinogenesis is a multistage proc Genetic ess involving multiple genetic and epigenetic Change events in protooncogenes. tumor suppressor genes, and anti-metastasis genes. 'INITIATEDv â€”/ rÃ¯Ã¯t$< 'CLINICAL

inhiortion NORMAL CELL PRENEOPLASTIC CANCERâ€¢CELL LESIONMALIGNANT TUMORP*

Activation of Proto-Oncogenes â€¢Inactivation of Tumor Suppressor Genes â€¢Inactivation of Antimetastasis Genes effects (64). Although interspecies differences have long been qualitative extrapolation of carcinogenesis data from laboratory known in the metabolism of xenobiotics (65-69), the metabolic animals to the human situation. Quantitative and qualitative pathways of activation and the resultant carcinogen-DNA ad differences in cytochrome P-450 enzymes in various tissues (70) ducts are generally qualitatively similar among various animal may be partly responsible for the divergent sites of cancer species, including humans (6). These observations support the induction among animal species; e.g., 4-aminobiphenyl causes 5026s

Hypothesis In Vivo Studies In Vitro Studies Generation Explant v Culture

Clinical Cell Observation Culture Molecular (epithelial) Carcinogenesis Fig. 2. Strategy for studies of molecular carcinogenesis and molecular epidemiology to improve interspecies extrapolation of carcino genesis data and to identify high cancer risk Molecules individuals. Epidemiology

Molecular Dosimetry Clinical Investigations of Carcinogen Exposure

Molecular Epidemiology Inherited Cancer Predisposition

liver cancer in rodents and bladder cancer in dogs and humans adducts has provided a mechanistic explanation of the muta- (65) and may confound tissue site-specific extrapolation of genicity of many carcinogens, including their mutational spec carcinogenesis data among animal species. Quantitative differ tra, and a rationale for improved carcinogen exposure assess ences in carcinogen metabolism and in the formation of carcin- ment in molecular epidemiological studies of human cancer. ogen-DNA adducts are, however, found among different cell types (71, 72), tissue types (6, 70, 73), and outbred individuals Critical DNA Targets: Protooncogenes and Tumor of the same species (74, 75). As discussed (see below) in the section "Molecular Epidemiology of Human Cancer," these Suppressor Genes quantitative differences may influence tissue site of cancer and Protooncogenes are normal cellular genes that, when inap an individual's cancer risk. propriately activated as oncogenes, cause dysregulation of The influence of carcinogen metabolism on interspecies ex growth and differentiation pathways and enhance the probabil trapolation of carcinogenesis data is becoming more well de ity of neoplastic transformation. Carcinogens can cause the fined by the cloning of genes encoding enzymes involved in genetic changes that can lead to activation of protooncogenes, activation and detoxication of chemical carcinogens. Investi including base substitution mutations (84), chromosomal trans- gators have recently cloned more than 150 CYP4 genes (76) locations (85), and gene amplification (45, 86). For example, and other genes involved in carcinogen metabolism, such as ras protooncogenes are activated primarily at codons 12, 13, human /V-acetyltransferase (77), human epoxide hydrolase (78, and 61 by base substitution mutations caused by chemical and 79), human NAD(P)H:menadione oxidoreductase (80), human physical carcinogens in both cultured mammalian cells and glutathione 5-transferases (81), and pig flavin-containing mon- animal models (87-90) including transplacental exposure to ooxygenase (82). As discussed by Gonzalez et al. (70), interspe chemical carcinogens (91). Mutation of the Ha-ras protoonco cies differences in carcinogen metabolism may, in part, be due gene is an early event in rodent models of skin and mammary to: (a) qualitative differences in CYP genes due to an absence carcinogenesis (87, 92). In addition, the v-Ha-ras transgene can of a CYP expression in an animal species; (b) quantitative and substitute for the initiation step in mouse skin carcinogenesis qualitative variations in regulation of CYP genes among animal in transgenic mice (93, 94). This animal model should be useful species; and (c) differences in CYP substrate or product speci for investigating the molecular mechanisms of tumor promoters ficity. Since examples of interspecies differences in each of the and antipromoters. 3 types noted above have been described, in vitro model systems In contrast to protooncogenes, tumor suppressor genes are including those using human cells and tissues (6) or genetically normal cellular genes that, when inappropriately inactivated, engineered cells or rodents containing single or combinations cause dysregulation of growth and differentiation pathways and of human genes directing the expression of specific enzymes enhance the probability of neoplastic transformation. Based on responsible for carcinogen metabolism (70, 83) will serve as a bridge between in vivo studies in animal models and the human Table 2 Examples offunctions of putative tumor suppressor genes situation (Fig. 2). Induce terminal differentiation The molecular and atomic analyses of the physical interac Maintain genomic stability tions between chemical carcinogens and DNA represent a major Trigger senescence Induce programmed cell death achievement of cancer researchers in the last two decades (84). Regulate cell growth The information gleaned from these studies of carcinogen-DNA Signal transducers of negative growth factors Regulators, e.g., PTPase7. of tyrosine kinases 4The abbreviations used are: CYP, cytochrome P-450; CHO, Chinese hamster Inhibit proteases ovary; BPDE, benzo(a)pyrene diol-epoxide; PKC, protein kinase C; TPA, 12-O- Alter DNA methylase activity tetradecanoylphorbol-13-acetate; AHH, aryl hydrocarbon hydroxylase; GST, glu Modulate histocompatibility antigens tathione S-transferase; PAH, polycyclic aromatic hydrocarbon; HPLC, high Regulate angiogenesis Facilitate cell-cell communication performance liquid chromatography; PTPase y, protein-tyrosine phosphatase y. 5027s

the multifunctional classes of tumor suppressor genes (Table 2) In both exogenous and endogenous types of target genes, the their number may equal that of the oncogenes. Loss of function carcinogen-induced mutational spectra can be compared to the of the products of both alÃelesisthe basis of the 2-hit hypothesis spontaneous mutational spectrum. The majority of sponta and the recessive nature of the genetic process (95). In addition neous mutations analyzed in these assays are single base sub to inactivation of both alÃelesby mutational mechanisms (base stitutions. However, interesting differences have been observed substitution mutations, deletions, chromosomal nondisjunc- in the spontaneous mutational spectrum in the endogenous aprt tion, and recombination) (96), inactivation of a normal alÃele of CHO cells compared to bacterial cells and exogenous genes by genomic imprinting (97) and its gene product by an increased carried by shuttle vectors in mammalian cells (111). Transitions rate of proteolytic digestion (98) or dominant negative mecha of G:Câ€”Â»A:Tarefrequent in CHO cells suggesting deamination nisms (99) have been proposed. Based on target size theory, the of 5-methylcytosine and/or DNA replication errors, whereas inactivation of a single alÃeleofa tumor suppressor gene should deletions and insertions are more frequent in the other assay have an intrinsically higher probability than activation of a systems. A comparison of the spontaneous mutational spectrum protooncogene, e.g., one of the ras protooncogenes in which at the aprt locus in CHO cells with the spectra induced by mutations in only a few specific codons will lead to activation. ionizing radiation, UV radiation or benzo(a)pyrene diol epox- The requirement for inactivation of both alÃelesof a tumor ide is shown in Table 3. The mutational spectrum of UV light suppressor gene counterbalances this probability except in those is consistent with the mutagenesis models of the promutagenic cases in which an inactivated alÃeleis inherited or the mecha cyclobutane and pyrimidine:pyrimidone (6:4) photoproducts nism of inactivation is via a dominant negative mechanism, as induced by UV light. As noted previously, ionizing radiation is proposed for the p53 tumor suppressor gene (99, 100). most efficient in causing deletions. BPDE, which binds to the Ionizing irradiation and carcinogenic hormones, metals, al 2-amino group of G, produces the predicted G:Câ€”Â»T:Atrans- dehydes, or fibers such as asbestos are generally inefficient in versions; a similar mutational spectrum for BPDE has been the production of point mutations at the gene level but are observed in human cell assays (112). Polycyclic aromatic hy more efficient at causing chromosomal abnormalities and losses drocarbons can also cause mutations at regions of the genes (62). Therefore, one would speculate that tumor suppressor encoding pre-mRNA consensus splice sites, resulting in mRNA genes would be targeted by these carcinogens more readily than splicing defects. For example, mutations affecting splicing in protooncogenes. Whereas many electrophilic metabolites of the CHO dhfr gene were preferentially induced by 3Â«,4ÃŸ-dihy- chemical carcinogens form carcinogen-DNA adducts and cause droxy-1 a,2Â«-epoxy-1,2,3,4-tetrahydrobenzo(c)phenanthrene point mutations, chemical carcinogens also cause chromosomal (113). The hprt locus is of particular interest because of the abnormalities and micronuclei. Thus, both cytogenetic and potential to compare mutational spectra obtained from studies mutagenesis assays have been developed to assess these muta using cultured cells experimentally exposed to carcinogens with tional changes (44, 101-103). those observed in human lymphocytes obtained from donors exposed in vivo to environmental carcinogens (114). Mutational Spectrum The molecular analysis of mutationally activated ras protoon cogenes in animal models of carcinogenesis generally supports Since mutations are largely responsible for activating pro the concept of mutational spectrum reflecting the DNA adduci tooncogenes and inactivating tumor suppressor genes, the mu formation and mutagenic activiiies elicited by specific chemical tational spectra of chemical and physical carcinogens are of carcinogens. For example, the mulalions found in activated ras interest to define endogenous and exogenous mutational mech protooncogenes associated with tumors of rodents exposed lo anisms. Studies using prokaryotic and simple eukaryotic assays Ihe melhylaling AAnilroso compounds are predominancy and site-specific mutagenesis assays (104, 105) have shown that G:Câ€”Â»A:Tbasesubslitutions (Table 4); these are likely due lo each carcinogenic agent produces a "fingerprint" (106) linking melhylalion of deoxyguanine al ihe Oh posilion followed by specific types and locations of DNA adducts with the muta mispairing wilh ihymine during DNA synthesis (92, 110, 115- tional spectrum of the agent. Both exogenous genes, which are 117). Although there are several deoxyguanine residues in ras introduced into the appropriate host cell by a shuttle vector codons lhal would generale a transforming protein if substi- (105, 107-110), and endogenous genes (106) such as adenine luled wilh adenine, Ihe animal experimenls have revealed lhat phosphoribosyltransferase (aprt), dihydrofolate reducÃase the mutalions occur overwhelmingly al only one of the "possi (dhfr), and hypoxanthine-guanine phosphoribosyl transferase ble" mutation sites. However, preferential mutalion siles are (hprt) have been utilized in the eukaryotic studies. These assays within the admittedly narrow range of possibilities for aclivaling will underestimate the mutational frequency due to deletions, ras genes. Unexplained mutational specificities have been ob chromosomal nondisjunction, and frame-shift mutations be served in other experimental systems (118-120) and may reflect cause other genes essential for cell survival may be adjacent to the differences in the spectrum of promulagenic carcinogen- the hemizygous nonessential detector gene. In addition, certain DNA adducls, specificily of DNA repair enzymes (121), and/ mutations may cause either clonal expansion or inhibition of or Ihe resullanl amino acid changes are eilher silent or lethal. the mutant cell and further complicate the interpretation of the Allhough the mutalional speclrum of ras prolooncogenes in mutational spectrum. rodent tumors caused by methylaling carcinogens is consistent

Table 3 Percentage distribution of mutations in the endogenous aprt locus, including multiple events in Chinese hamster ovary-cells"

TransitionsMutagenSpontaneous C:G3 C:G0

UV radiation 2 S662TransversionsG:Câ€”10 5 12 2 2 Ionizing radiation 6 614A:Tâ€” 19 13 315Insertions0 05 Benzo(a)pyrene diol epoxideG:C-Â»A:T71615A:T-Â«:C00G:Câ€”T:A13 0A:T-Â»T:A7 9Deletions6 'Adapted from Ref. 106. 5028s

Table 4 Examples of predominant base substitution mutations in ras protooncogenes in rodent tumors

Lung Mammary Skin Lung(K-ras) ConditionSpontaneousMethylating(H-ras)!G35â€” (H-ras)C'Â»-.A(H-ras) (K-ras) (H-ras) (K-ras)G3'-^A*RatMammary(H-ras)G35â€”A*(NMU)Kidney(H-ras)(DMN-OMe)Esophagus(H-ras)G3'-Â»AJ(MB) G3!-Â»TG3'^A/

carcinogen''Tetranitromethane Â»A'(NMU, * MNNG)MouseLiver (NNK, DMN)Liver

Benzo(a)pyreneSkin 7,12-Dimethylbenzanthracene Aflatoxin B,

Benzidine and congeners

Urethan AiÂ«_TÂ» An " Ref. 457. * Ref. 458. ' Ref. 459. ''NMU, jV-methyl-A"-nitrosourea; MNNG, /V-methyl-iV'-nitrosoguanidine; NNK, 4-(methylnitrosamine)-l-(3-pyridyl-l-butanone), DMN, A'-nitrosodimethyla- mine; DMN-OMe, methyl(methoxymethyl)nitrosamine: and MB, jV-nitrosomethylbenzylamine. ' Ref. 87. /Ref. 460. 'Ref. 461. * Ref. 117. 1Ref. 462. ' Ref. 467. * Ref. 463. 'Ref. 150. " Ref. 464. "Ref. 139. Â°Ref.465. ' Ref. 466. * R. W. Wiseman, personal communication. 'Ref. 139.

Table 5 Examples of human cancers with base substitution mutations in the pS3 tumor suppressor gene"

ofmutationsdetected atA:T65712131903G:C372632251712341217CpG-TpG74267052579G:C-A:T121331163730815G:C-T:A19709142221G:C-C:G661013221 V\orldwidecancer in tumor burden(rank)*234781112CancerLungBreastColonEsophagusLiverBladderLeukemiacelllinesand 'hotspots"(codon)273175.248273, tumors^43"31393719'15531220Mutational

282249273Mutations

andlymphomasSarcomasBrainNo.

Â°Hollstein et al. (132). * From Muir (468). ' Only mutations in exons 5, 6, 7. and 8 are included in this analysis. Tumor cell line mutations are included in the analysis with the understanding that some of these may have arisen in vitro. d Chiba et al. (136) reported a higher p53 mutation frequency in lung squamous cell carcinoma than in other non-small cell lung carcinomas. ' Frequency and mutational spectrum may vary considerably with geographic origin of tumor. with the formation of the promutagenic 06-melhyldeoxyguano- The mutalional speclra of aclivaled ras prolooncogenes in sine and mutational spectrum caused by A/-nitroso-/V'-methyl- lumors and preneoplaslic lesions caused by chemical carcino urea in the aprt gene of CHO cells (106), an alternative hypoth gens in animal models (Table 4) may prove lo be inslructive in esis is that the mutant ras genes preexist in certain cells and the inlerprelalion of mulalions in prolooncogenes and tumor that exposure to the methylating agent facilitates clonal expan suppressor genes found in human cancers (Table 5). The spectra sion of these mutant cells. This latter hypothesis has been tested of Ki-ras protooncogene mutations in human adenocarcinomas by investigating the induction of rodent tumors by chemical vary according lo lissue sile; e.g., G:Câ€”Â»T:Atransversionsoccur carcinogens that form DNA adducts with differing chemical in lung tumors, whereas G:Câ€”Â»A:Ttransitions predominale in specificity. As seen in Table 4, the mutational spectra were colonie lumors. The inlerprelalion of Ihese results, however, highly correlated with each chemical carcinogen and reflected may be confounded by sponlaneous mulalions engendered by the predicted base substitution (84), i.e., G:Câ€”Â»T:Atransversion eilher endogenous mulagens or DNA polymerase errors. As for benzo(a)pyrene which forms predominantly the /V2-BPDE- two examples, 8-hydroxyguanine, caused by oxy radical damage deoxyguanosine adduci (122) and A:Tâ€”>T:Atransversion for (124) and DNA depurination, can produce G:Câ€”Â»T:Airansver- 7,12-dimethylbenzanthracene which forms predominantly the sions, and DNA polymerase infidelity will also produce G:Câ€”Â» A*-7,12-dimethyIbenzanthracene diol-epoxide-deoxyadenosine T:A transversions as well as olher changes (125). adduci (123). The p53 lumor suppressor gene is ideally suiled for analysis 5029s

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1991 American Association for Cancer Research. CARCINOGENESIS of mutational spectrum: (a) p53 is well conserved in evolution cancer, the mutational spectra of Ki-ras and/or the p53 gene (126) and 5 domains are >90% homologous in DNA sequence could be compared to bronchogenic cancers, including the use among humans and rodents that are frequently used in animal of paraffin-embedded, fixed archival tissue, from cigarette models of carcinogenesis; (b)p53 is mutated in diverse types of smokers versus nonsmokers, and from workers in high risk human cancer (127-131) and, where examined, cancers in occupations, e.g., uranium mining, mustard gas production, laboratory animals5"7; (c) a wide spectrum of mutational types asbestos mining, and chloromethyl ether production. and codon sites have been observed that presumably define regions of the p53 protein likely to be essential for its biological Selective Clonal Expansion activity in cell cycle control, in tumor suppression, and for its interaction with other cellular and viral proteins. A recent The majority of human cancers and those induced by chem review (132) has concluded that the majority of the mutations ical and physical carcinogens in animal models are unicellular in human tumors occur in the evolutionarily highly conserved in origin (43, 140). The clonal nature of neoplasia is the domains in exons 5-8 of the p53 gene, and the missense cornerstone in the concept of multistage carcinogenesis and mutations are predominantly transitions at G:C base pairs and provides the basis for current strategies designated to elucidate are almost all (>95%) at amino acids that are entirely conserved the component genetic changes. If all of the clonally derived in mouse, rat, monkey, and human. Mutational spectra also cells in a tumor, although heterogeneous in other aspects (dis vary among cancer types (Table 5). The G:Câ€”Â»A:Ttransitions cussed below), have in common the critical genetic lesion(s) are the most frequent in colon tumors and 68% of the mutations that triggers and/or drives their selective clonal growth then occur at CpG dinucleotides. These findings are consistent with the identification of this lesion(s) is a realistic goal. the endogenous mutational mechanism due to deamination of Recent data suggest that alterations in thep53 and Rb tumor 5-methylcytosine residues found at CpG dinucleotides in the suppressor genes represent such critical genetic lesions. For mammalian genome. More than one-half of the p53 mutations example, germline mutations in the Rb gene predispose to in colon tumors are at "hot spots," codons 175, 248, 273, or retinoblastoma (95, 96) and similar mutations in the p53 gene 282, each of which is a CpG dinucleotide. confer an inherited susceptibility to cancers of the breast, soft In contrast to colon tumors, CpG dinucleotides are less tissues, brain, and other tissues (141, 142). In vitro transfection frequently sites of mutations in most other types of human of wild type p53 into neoplastic colon (143), bladder (144), cancers. Whereas G:Câ€”>T:Amutations are rare in colon tu brain (145), and bone (146) cell lines containing an endogenous mors, these transversions are significantly more common in mutant p53 gene suppresses cellular growth and/or tumori- breast and lung cancers. The G:Câ€”>T:Amutations in Ki-roj genicity. Similar transfection studies using putative wild type protooncogene are also found in human lung adenocarcinomas Rb have also suppressed, to varying degrees, cell growth (147, (133-135) and in rodent lung cancers caused by benzo(a)pyrene 148). Although the mechanism(s) of growth retardation of these (Table 4). Interestingly, the p53 mutational spectra differ in cell lines by p53 or Rb is uncertain, the inhibition of the cell small cell lung cancer and non-small cell lung cancer; G:Câ€”Â»cycle progression into S phase following induction of wild type T:A transversions are common in the latter group of cancers p53 is accompanied by selective down-regulation of mRNA and (136). Whereas CpGâ€”Â»TpGmutations occur with intermediate protein expression of proliferating cell nuclear antigen, a cofac- frequency in esophageal cancers, 36% of the mutations are at tor of DNA polymerase Â¿,an important component of DNA A:T pairs which may be due in part to DNA depurination and/ replication (149). or exposure to chemical carcinogens such as urethan (Table 4), Studies of animal models suggest that certain activated pro- a contaminant of certain alcoholic beverages. tooncogenes may also be candidate critical genes. Mutations in The most striking p53 mutational spectrum is found in hep- the Ha-ras protooncogene are early genetic events in mouse atocellular carcinomas from either Qidong, People's Republic skin carcinogenesis (150) and rat mammary carcinogenesis (151, 152). Certain oncogenes impart, as transgenes, an "initi of China (137) or southern Africa (138). Eleven of 12 base ated" state (93, 94), and cooperation among oncogenes has substitution mutations in 26 tumors were at a single site, the 3rd base position of codon 249, and all but 1 were G:Câ€”>T:A been shown to increase cancer risk in transgenic mouse models transversions. One additional mutation at codon 157 was also (153). Whereas germline mutations occur in tumor suppressor a G:Câ€”>T:Atransversion. These tumors were from patients genes that increase cancer risk in the affected individuals (141, who live in geographic areas where aflatoxin B, and hepatitis 142), germline mutations that activate protooncogenes in hu B virus are major risk factors. Aflatoxin B, is a naturally mans have yet to be described. The success of transgenic mouse occurring hepatocarcinogen that forms /V7-deoxyguanosine pro- studies argues against the possibility that such mutations would mutagenic adducts and induces primarily G:Câ€”Â»T:Atransver lead to fetal death and thus not be observed in the human sions and G:Câ€”Â»A:Ttransitions in experimental systems (139) population. (Table 4). Analysis of liver tumors from geographical areas Activated protooncogenes can modulate the responsiveness of mammalian cells to their microenvironment and their cellu where aflatoxin BI is considered not to be a significant risk lar neighbors. For example, rodent cells transformed by certain factor will be instructive in determining whether exposure to transfected oncogenes have defective intercellular communica this fungal carcinogen may be responsible for these p53 tion (154) and the EIA oncogene induces resistance to the mutations. growth-inhibitory effects of transforming growth factor ÃŸ, An analysis of mutational spectra in human tumors from (155). When Ha-ras, Ki-ras, or the combination of c-myc and populations with differing risk factors may provide insight in a c-ra/are transferred into SV40 T "immortalized" human bron manner similar to those of the studies in experimental animals chial epithelial cells (BEAS-2B), the cells had a reduced respon described above (Table 4). In addition to further studies of liver siveness to growth inhibition by either transforming growth '' A. Balmain, personal communication. factor type ÃŸor serum (156-158)* and thus have potentially ' A. Klein-Szanto. personal communication. 7G. Wogan, personal communication. * Unpublished results. 5030s

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1991 American Association for Cancer Research. CARCINOGENESIS gained a selective clonal expansion advantage. Antisense oli- okadaic acid, a potent inhibitor of protein phosphatases I and gonucleotides or expression vectors producing antisense DNA IIA (178, 179). The interpretation of the above studies is fragments of the mRNAs of these oncogenes should be useful restricted because of the intrinsic limitations of experimental in assessing the direct role of raÃ,myc, or ra/in the modulation designs using agonists and/or inhibitors that frequently have of growth and differentiation in this in vitro model system of multiple nonspecific effects. Since members of the PKC and human bronchial epithelial carcinogenesis. the protein phosphatase multigene families are being cloned, The molecular mechanisms responsible for selective growth more powerful genetic strategies are becoming available. advantage of initiated cells are likely to be numerous and involve cell-cell interactions (154), cell-matrix interactions (159), cell- Genomic Instability growth factor interactions (34, 160) and intrinsic aberrations in regulation of the cell cycle (161), terminal differentiation Normal human somatic cells maintain a diploid karyotype and have a mutation frequency of about 10~8 for hemoglobin (41), and programmed cell death (162). Deregulated expression of Bcl-2, a novel inner mitochondrial membrane protein, ex variants (point mutations), about 10~7 for hprt variants (meas tends the survival of lymphoid cells presumably by blocking ures many classes of mutations, but the assay does not detect mitotic recombination), and about 10~5 for glycophorin A or programmed cell death, apoptosis, and, as a hybrid minigene with an immunoglobulin gene, increases the probability of HLA variants (measures most classes of mutations including lymphoma in transgenic mice (163). Epstein-Barr viral late somatic recombination, gene conversion, or chromosomal non- gene products may also extend the survival of B-lymphocytes disjunction) (114, 180, 181). by blocking their death by apoptosis (164). An example of a The potential sources for these observed mutation frequencies study that has identified candidate mutant genes and/or re include exposure to "background" levels of environmental versed the neoplastic state by transfecting the wild type gene is chemical and physical agents and endogenous mechanisms (55) the transfection of Â«5and/3Â¡integrincomplementary DNA into such as: (a) the chemical instability of DNA, e.g., depurination malignant CHO cells with a much decreased intrinsic level of [one can calculate that each cell undergoes IO4 depurinations/ these cognate integrins leads to suppression of tumorigenicity day (125)] or deamination of 5-methylcytosine to yield thymi- (165). Indirect proof of mechanisms leading to abnormal cell- dine (182, 183); (b) free radicals of oxygen, e.g., hydroxyl ions growth factor interactions include interruption of signal trans- [from measurements of 8-hydroxyguanine and thymine glycol duction pathways of positive growth factors by use of neutral in urine, about IO4 oxy radical-induced DNA lesions occur in izing antibodies to either growth factors, e.g., gastrin-releasing each human cell per day (54)]; and (c) DNA replication errors. peptide (166), or their cell membrane receptors, e.g., epidermal Imbalances in deoxynucleoside triphosphate pools (184) and growth factor receptor (167), resulting in decreased tumori mutations in DNA polymerase Â«(185) are examples of mech genicity of the human carcinoma cells injected into athymic anisms leading to infidelity of DNA synthesis. Inactivation of nude mice. Transfection of antisense oligonucleotides or vectors RAD18, a putative DNA repair gene in Saccharomyces cerevis- expressing antisense oligonucleotides of certain oncogenes may iae, leads to an increase in the frequency of G:Câ€”>T:Atrans- lead to a reversal of certain in vitro phenotypes, such as soft versions (186). Considering the multiplicity of proteins involved agar growth or transformed morphology, and in some cases in DNA synthesis, DNA repair, mitosis, and the cell cycle, the cause a decrease in tumorigenicity (168-172). number of potential gene targets in somatic cells is large and Protein kinase and protein phosphatases are responsible for could result in the mutator phenotype (43, 55, 187) (Table 6) the reversible phosphorylation of cellular proteins that control that could increase the probability of both neoplastic transfor growth and differentiation of mammalian cells (173,456). PKC mation and the generation of more malignant subclones during is a multigene family with at least 8 members that have differ tumor progression (42, 188). If such mutations occur in germ ential expression in specific tissue types and functions in signal cells and are nonlethal, they could lead to congenital abnor transduction (28, 174). Exposure of certain cells to the tumor malities and increased cancer risk in an inherited manner. The promoter TPA causes PKC to translocate to cellular mem hypothesis that genomic instability may have an inherited basis branes and the resultant activation of PKC isoforms is associ and be associated with increased cancer risk is supported by ated with rapid induction of expression of nuclear protoonco- studies of Bloom's syndrome, where an increase in cytogenetic genes c-jun and c-fos (175). Since exposure to TPA produces end points is observed (189), and of colonie carcinomas, where many phenotypic responses that are cell type dependent (176), a significant increase in allelic deletions are found in tumors and activated PKC modulates cytosolic calcium concentration from patients who have first degree relatives with cancer (190). and phosphorylates multiple protein substrates, the signal Cytogenetic studies (191, 192) have provided the bulk of the transduction pathways involving PKC are difficult to delineate indirect evidence supporting the hypothesis that genomic insta (28). One hypothesis of the mechanistic role of PKC in tumor bility is a potential mechanism driving tumor progression. The promotion in mouse skin carcinogenesis is that certain proteins, evidence is less compelling (193) when the frequencies of either when phosphorylated at specific sites directly or indirectly by spontaneous point mutations (194-201) or drug-induced gene PKC, activate signal transduction pathway(s) positive for cell amplification (202-206) are compared in normal and neoplastic growth. Assuming that the phosphorylated protein(s) is in the cells. hypothetical active state, dephosphorylation at specific sites Recombinase infidelity (207), telomere reduction (208), and would lead to inactivation. Therefore, inhibitors of the respon DNA hypomethylation (47, 209) are examples of additional sible protein phosphatase(s) would increase the steady state mechanisms of genomic instability. The frequency of somatic levels of the critical phosphoprotein(s) in the activated state recombinational events at certain loci, e.g., Â¡mmunoglobulin and would be candidate tumor promoters. Although the phos- genes, is relatively high, but specific DNA sequences at these phoprotein(s) critical in tumor promotion has not as yet been loci are recognized by the responsible V-(D)-J recombinases. identified, this latter hypothesis is supported by the recent Although the degree of infidelity of wild type and mutant discovery of non-TPA-like tumor promoters (177) such as recombinases is not known, a possible example of "illegitimate" 5031s

Table 6 Examples of gene abnormalities associated with genomic instability Genomic inslabilily GeneRAD 9RAD cererisiaeS. lossBase 18p}4Â«"Topoisomerase cerevisiae.9. transversion)AneuploidyAbnormalsubstitution (G:Câ€”>T:A pombeS. IInodDNA pombeDrosophilaHumanHuman segregationAbnormalchromosomal segregationBasechromosomal Â«p53R.4C-IseidUnknownSpeciesS.polymerase substitutionAneuploidyChromosomal syndrome)HumanMurineHuman(Li-Fraumeni deletionsAberrantrearrangements and double-strandbreakt'(D)J recombination and repairHyperrecombinationDNA (Bloom's syndrome)ActivationMutationMutationMutationMutationMutationMutationMutationMutation"MutationUnknownTypeChromosomal ' In vitro experimental studies.

V-(D)-J recombinase activity leading to interstitial deletion and populations frequently acquire the risk of cancer prevailing in rearrangements in a growth-regulatory gene has been described their new geographic location of residence (1, 2, 219). Based (210). In addition, the seid (severe combined immunodeficiency) on the above and other considerations (1), it has been estimated mutation in mice is due to a defect in the site-specific V(D)J that about 80% of all cancer in the United States is due to recombination pathway and has been recently linked to a defi environmental factors. Finally, one can speculate that the rates ciency in double-strand break DNA repair. This linkage sug of spontaneous mutations, e.g., deamination of 5-methylcyto- gests that the seid gene product performs a similar function in sine, may be altered by environmental chemicals directly and/ both pathways. or indirectly via generation of endogenous agents such as oxy Hastie et al. (208) have shown that telomere reduction is radicals and the intracellular signal transducer, nitric oxide. common in both colorectal adenomas and carcinomas and have speculated that telomere reduction may be involved as an early Molecular Epidemiology of Human Cancer event in carcinogenesis. Interestingly, studies of yeast (211) and maize (212) have shown that chromosomes without terminal Combined laboratory-epidemiological studies of human can repeats or telomeres are prone to rearrangements or loss. Stud cer have a long history and have been named metabolic (220), ies in yeast have also identified genes involved in cell cycle biochemical (221), and molecular epidemiology (222). Whereas control and mitosis, e.g., RAD9 and cdc-2, that, when mutated, classical epidemiology has been successful in identifying high influence the fidelity of mitosis (213, 214) (Table 6). For cancer risk populations, e.g., cigarette smokers, the primary example, certain mutations in RAD9 of 5. cerevisiae increase goal of molecular epidemiology is to identify individuals in the rate of chromosomal loss by 7-21-fold (215) and topoisom- these populations who are at the highest cancer risk. The erase II mutants in Saccharomyces pombe have abnormal seg current strategy involves improved exposure assessment by regation of the intertwined daughter chromosomes at the end measuring biologically effective doses of carcinogens and sec of DNA replication (216) and abnormal chromosome conden ondly, analysis of host susceptibility factors within the frame sation (217). Since human homologues of such genes are being work of well-designed epidemiological studies (223). identified, similar investigations could be conducted using cul tured human cells, and human tumors could be examined for Exposure Assessment mutations in these genes. Analogous to the yeast paradigm of a mutator phenotype Carcinogen-macromolecular adducts, mutations, and cyto- associated with dysregulation of cell cycle control (213), certain genetic changes can be measured in the target epithelial cell activated protooncogenes or inactivated tumor suppressor population and in surrogate blood cells as shown in Fig. 3. This genes could lead to genomic instability. The rapid appearance paradigm is now feasible to explore experimentally because of of aneuploidy and "spontaneous" immortalization of cultured recent advances in methods to measure carcinogen-macromo- human fibroblasts from donors with the Li-Fraumeni syn lecular adducts (224), somatic gene mutations (181, 225), and drome, who have an inherited mutant p53 alÃele(218), is cytogenetic endpoints (103). In addition, polymerase chain consistent with this hypothesis. The genomic instability caused reaction technology and DNA sequencing allows a rapid as by certain DNA viruses such as SV40, adenovirus, and papil- sessment of mutations in protooncogenes, tumor suppressor lomavirus could also be due to the inactivation of p53 and/or genes, and antimetastasis genes in the epithelial cells. Since the Rb by complexing with the viral proteins. ras protooncogene family is occasionally and the p53 tumor As argued by Loeb (55), the impression of a high degree of suppressor gene is frequently mutated in human cancers, as genomic stability may be misleading when one considers that discussed above, these genes are suitable candidates for assess the human body contains about IO14cells and that, within the ing the genetic consequences of carcinogen-DNA adducts and average human life span, the cells undergo a total of IO'6 endogenous mutagens. The mutational spectra in ras and p53 divisions. Therefore, spontaneous mutagenesis may signifi genes can be measured by current technology due to the clonal cantly contribute to the prevalence of certain cancer types that expansion of the cells driven by these mutant genes. Although have no apparent risk factors and minimal variations in inci small clonal populations of a few hundred cells are sufficient dence occur among different geographic areas. However, epi for analysis of mutational spectra by polymerase chain reaction demiolÃ³gica! studies have: (a) identified significant cancer risk and direct DNA sequencing, additional advances in methodol factors, e.g., tobacco smoke and hepatitis B virus; (b) found ogy will be required to determine the mutational spectra in substantial geographic variation in the incidence of the most single cells that have not clonally expanded and are diluted in common types of human cancer; and (c) found that migrant a much larger population of normal cells. 5032s

Host Susceptibility Factors Table 7 Examples of inherited predisposition of human cancer Candidate of Both inherited and acquired host factors that predispose an genesP53RbMCCCYP2D6XPACConditionLi-Fraumeni cancertypeCarcinomas individual to cancer caused by environmental agents have been syndromeFamilial thebreast of identified (37, 226). Inheritance of a germline mutation in the and blad der;sarcomasRetinoblastomaColonLungSkin tumor suppressor genes, p53 (141, 142) or, perhaps, Rb (227), retinoblastomaFamilial predisposes to the development of adult types of cancer (Table coliExtensivepolyposis 7). Other inherited host susceptibility factors include certain debrisoquine phe notypeXeroderma DNA repair deficiencies (228), genetic polymorphism in certain pigmentosum AExamples xenobiotic metabolizing enzymes (70), and, perhaps, the prooxidant state in Bloom's syndrome (229). cogenes and inactivate tumor suppressor genes in replicating Interindividual Variation in Human Carcinogenesis cells. The steady state levels of these adducts depend on both the amount of ultimate carcinogen available to bind and the No one supposes that all the individuals of the same species are rate of removal from DNA by enzymatic repair processes. The cast in the very same mould. These individual differences are genomic distribution of adduct formation and repair is nonran- highly important for us. ... dom and is influenced by both DNA sequence and chromatin The Origin of Species structure (121, 233-235). Charles Darwin, 1859 Carcinogen Metabolism and DNA Adduct Formation. Chem ical carcinogens are metabolized by a wide variety of soluble Scientists have repeatedly recognized person-to-person dif and membrane-bound enzymes. Multiple forms of human cy- ferences in behavior, morphology, and risk of disease. Such tochrome P-450 are involved in the oxidative metabolism of interindividual differences may be either inherited or acquired. chemical carcinogens, e.g., polycyclic aromatic hydrocarbons For example, inherited differences in susceptibility to physical (70). Several thousand-fold interindividual variation has been or chemical carcinogens have been observed among individuals, observed in placental AHH activity which is catalyzed by the including an increased risk of sunlight-induced skin cancer in CYPIA1; some of this variability is under direct genetic control, people with xeroderma pigmentosum (228), bladder cancer in but variations are also the result of an enzyme induction process dye stuff workers with a poor acetylator phenotype (230), and due to maternal exposure to environmental carcinogens, e.g., bronchogenic carcinoma in tobacco smokers who have an ex tobacco smoke, or dietary factors (236-238). However, the tensive debrisoquine hydroxylator phenotype (231, 232). induction process itself may have a genetic component (239) Because most chemical carcinogens require metabolic acti and inducible AHH activity is higher in cultured lymphocytes vation to exert their oncogenic effects and the amount of from lung cancer cases when compared to controls (240). Trell ultimate carcinogen produced results from the action of com and coworkers (241) are currently conducting a prospective peting activation and detoxication pathways, interindividual study to determine if high inducibility of AHH is a risk factor variation in carcinogen metabolism is considered to be an for the development of cancer. Increased binding of important determinant of cancer susceptibility (75). DNA ad- benzo(a)pyrene metabolites to DNA in lymphocytes of patients ducts are one form of genetic damage caused by chemical with lung cancer versus noncancerous controls has also been carcinogens and may lead to mutations that activate protoon- observed-(242). A highly inducible allelic variant CYPIA1 has been identified in humans (243).9 This variant is associated

â€¢Environmental Exposure with increased risk of smoking-associated lung cancer in a J Japanese population (244). This association has not been found 1â€¢ in a U.S. population10. Bio1 odIâ€¢um Targetf Tissue (cell)Â»â€¢ Cytochrome P-450 (CYP2D6) activity is polymorphic and has also been linked to lung cancer risk (231, 232). CYP2D6 rbcsei wbcr hydroxylates xenobiotics such as debrisoquine, an antihyperten- *â€¢ir sive drug, and a tobacco-specific A'-nitrosamine (70), and an AdductsG.A.â€¢ Adducts1^â€¢ individual's polymorphic phenotype is inherited in an autosomal recessive manner. The rate of 4-hydroxylation of debriso quine varies several thousand-fold among people, and lung, â€¢Cytogenetic Cytogeneticâ€¢^CellClonal liver, or advanced bladder cancer patients are more likely to Endpointsâ€¢Â« EndpointsCellDonai have the extensive hydroxylator phenotype when compared to noncancer controls (231, 245, 246). In a case-control study of Expansionâ€¢ Expansionâ€¢ lung cancer in the United States, the extensive hydroxylator phenotype had an 8-fold increased cancer risk when compared Mutational Mutational to the poor hydroxylator phenotype and the increased risk was spectra, e.g., â€” *â€¢ spectra, e.g., HPRT, HLA-*nâ€¢ ras, p53 primarily for histolÃ³gica! types other than adenocarcinoma of the lung (232). In addition, analysis of data derived from a â€¢ExposureAssessment British population (231) has revealed that individuals with the Fig. Ã•.Molecular dosimetry, mutational spectra, and exposure assessment. extensive hydroxylator phenotype who are occupationally ex- Paradigm for improvement of carcinogen exposure assessment that involves the measurement of carcinogen-macromolecular adducts, cytogenetic end points, and 9T. L. McLemore, S. Adelberg, and M. C. Liu. Cytochrome P450IA1 gene mutational spectra in protooncogenes, e.g., ras. or tumor suppressor genes, e.g., expression in lung cancer patients: evidence for cigarette smoke-induced expres p53, found in target tissues and in monitoring genes, e.g., hprt or histocompati- sion in normal lung and altered gene regulation in primary pulmonary carcinomas, bility genes (HLA), in blood lymphocytes or glycophorin A (G.A.) protein in red submitted for publication. blood cells (rbc). IOP.Shields, A. Weston. and C.C. Harris, unpublished results. 5033s

posed to high amounts of either asbestos or polycyclic aromatic Although the major DNA adducts are qualitatively similar hydrocarbons have relative lung cancer risks of 18- and 35-fold, for the chemical carcinogens thus far studied in these in vitro respectively (247). CYP2D6 may activate a chemical carcino- models, quantitative differences have been found among indi gen(s) found in tobacco smoke, e.g., certain jY-nitrosamines, viduals and their various tissue types (73, 260, 269-271). The and/or, a more speculative possibility, inactivate nicotine, the differences in formation of DNA adducts range from approxi addictive pleasure component of tobacco smoke that would mately 10-150-fold among humans, the interindividual distri decrease its steadystate level and increase the drive to smoke bution is generally unimodal, and the variation is similar in more cigarettes. Thereby, the individual with the extensive magnitude to that found in pharmacogenetic studies of drug metabolizer phenotype would be at greater cancer risk. Another metabolism (75). hypothesis is that an alÃeleof the CYP2D6 gene is in linkage DNA Repair Rates. DNA repair enzymes modify DNA dam disequilibrium with another gene that influences cancer age caused by carcinogens in reactions that generally result in susceptibility. the removal of DNA adducts. Studies of cells from donors with The Â¿Y-acetylationpolymorphism is controlled by two auto- xeroderma pigmentosum have been particularly important in somal alÃelesat a single locus in which rapid acetylation is the expanding our understanding of DNA excision repair and its dominant trait and slow acetylation is recessive. Acetylation of possible relationship to risk of cancer (228). The rate but not carcinogenic aromatic amines has been proposed as a cancer the fidelity of DNA repair can be determined by measuring risk factor (248). The slow acetylator phenotype has been linked unscheduled DNA synthesis and removal of DNA adducts, and to occupationally induced bladder cancer in dye workers ex substantial interindividual variations in DNA repair rates have posed to large amounts of A'-substituted aryl compounds (230). been observed (272). As discussed above, the fidelity of DNA Interestingly, the rapid acetylator phenotype is commonly repair could also vary among individuals, and recent advances found in colon cancer cases (249). Whether or not this associ in the identification of mammalian DNA repair genes and their ation is due to metabolism of a carcinogenic aromatic amine in molecular mechanisms (273, 274) should provide an opportu the colonie epithelium is not known. nity to investigate the fidelity of excision DNA repair in the Wide interindividual differences in detoxifying enzymes of near future. In addition to finding excision repair rates severely carcinogens are also found. For example, at each step in the depressed in xeroderma pigmentosum cells (e.g., complemen metabolic pathway of benzo(a)pyrene activation to electrophilic tation group A), an approximately 5-fold variation among diol epoxides, competing detoxifying enzymes are found (250). individuals in unscheduled DNA synthesis induced by UV Confirming previous observations (251), a recent study of sev exposure of lymphocytes in vitro has been found in the general eral of the enzymes involved in benzo(a)pyrene metabolism population (272). A significant reduction in unscheduled DNA showed a more than 10-fold person-to-person variation in their synthesis induced in vitro by yV-acetoxy-2-acetylaminofluorene activities (252) and presented indirect evidence that tobacco has been observed in mononuclear leukocytes from individuals smoke induced many of these enzymes. Genetic control of the with a history of cancer in first degree relatives when compared presumed detoxication of benzo(a)pyrene by conversion to to those without a family history (275, 276). water-soluble metabolites has been reported (239). Interindividual variation has been noted in the activity of O6- GSTs are multifunctional proteins (253) that catalyze the alkyldeoxyguanine-DNA alkyltransferase; this enzyme repairs conjugation of glutathione to electrophiles, including the ulti alkylation damage to O6-deoxyguanine (277-280). In addition mate carcinogenic metabolite of benzo(a)pyrene (254), and are to these person-to-person differences of about 40-fold, wide considered to be a detoxification pathway of carcinogenic poly- variations in this DNA repair activity have been observed in cyclic aromatic hydrocarbons (255). The three isoenzymes of different types of tissues (277, 278, 281, 282), fetal tissues GST (Â«-<,n and w) vary in their substrate specificity, tissue exhibit 2- to 5-fold less activity than the corresponding adult distribution, and activities among individuals (256). Expression tissues (283), and cells may have lower repair rates after ter of GST-ji is inherited as an autosomal dominant trait (257) and minal differentiation (284). The activity of this DNA repair individuals with low GST-^ activity may be at greater risk of enzyme is inhibited by certain aldehydes (281) and alkylating lung cancer caused by cigarette smoking (258, 259). Further cancer chemotherapeutic agents (285). A decrease in this DNA functional and genetic studies of acquired and inherited defi repair activity has been observed in fibroblasts from patients ciencies in the activities of enzymes involved in the detoxifica with lung cancer when compared to donors with either mela tion of chemical carcinogens are warranted. noma or noncancer controls (286). Therefore, acquired and/or Metabolism of carcinogens from several chemical classes, inherited deficiency in 06-alkyldeoxyguanine-DNA alkyltrans including /V-nitrosamines, polycyclic aromatic hydrocarbons, ferase may be a cancer risk factor in tobacco smokers. hydrazines, mycotoxins, and aromatic amines, has been studied A unimodal distribution of repair rates of benzo(a)pyrene using human tissues, cells, and microsomes (73, 260-267). The diol-epoxide-DNA adducts has been observed using human enzymes responsible for the activation and deactivation of lymphocytes in vitro (287). The interindividual variation was procarcinogens, the metabolites produced, and the carcinogen- substantially greater than the intraindividual variation which DNA adducts formed by cultured human tissues and cells, in suggests a role of inherited factors. The influence of these general, are qualitatively similar among donors and tissue types. variations in DNA repair rates in determining tissue site and The DNA adducts and carcinogen metabolites are also similar risk of cancer in the general population remains to be to those found in most laboratory animals, an observation that determined. generally supports the qualitative extrapolation of carcinogen- Tumor Promotion. Because cancer is the result of complex esis data from the laboratory animal to the human (73). How interaction between multiple environmental factors and both ever, some notable differences among animal species have been acquired and inherited host factors, one should consider carcin- reported, including metabolism of aromatic amines in the ogen-DNA adducts as only one piece in the puzzle. Other pieces guinea pig (65), benzo(a)pyrene in the rat and rabbit (66, 268), include determinants of tumor promotion. In the skin carcino- and aflatoxin B, in the Syrian golden hamster (67). genesis studies, wide variations in susceptibility to tumor-pro- 5034s

moling agents have been observed among animal species and also been performed for coke oven workers in ihe United States among different inbred strains of a single species (288-291). and Scandinavian countries (308, 316). However, levels of Epidemiological studies suggest that tumor promotion may PAH-DNA adducts reported using the 12P-postlabeling assay influence both tumor probability and latency period in humans for detection are lower than those reported using enzyme im- (1), and mathematical models of carcinogenesis indicate that munoassay for deteclion. These dala can in pari be explained cell proliferation is an important determinant of cancer risk by ihe relalive subslrate specificities of each assay which have (292). Methods to identify human tumor promoters and to not yet been fully slandardized or rigorously compared. Anli- predict responses to tumor promoters among different humans PAH-DNA anlibodies that presumably indicate genotoxic ex need to be developed. posure to metabolically aclivaled PAHs have also been detected Interindividual Variation in Carcinogen-Macromolecular Ad- in human serum of both occupalionally exposed and nonex- ducts in People Exposed to Chemical Carcinogens. Results from posed populations (coke oven workers; smokers and non- in vivo and in vitro studies discussed above serve as a basis for smokers) (303, 304, 309). investigations in biochemical and molecular epidemiology. For Alkyl-DNA adducts have also been detecled in human sam example, the observation that the carcinogen-DNA adducts ples. The receÃ±Ãuseof HPLC or Â¡mmunoaffinily chromatog- formed in cultured human tissues are generally the same as raphy in combination with the 32P-postlabeling assay has re those found in experimental animals in which these chemicals vealed Ihe presence of 06-methyldeoxyguanosine, O6-ethyl- induce cancer has encouraged investigators to search- for DNA deoxyguanosine, O4-ethylthymidine, and 7V7-melhyldeoxy- adducts in biological specimens obtained from people exposed guanosine as well as other types of alkyl adducls in ihe human to either specific carcinogens such as benzo(a)pyrene or chem- population, including cancer patients (317-322). The combi otherapeutic agents. nation of HPLC and the "P-posllabeling assay has been used The development of highly sensitive methods to detect car- to detect O6mdG in lung cancer cases (320, 323) and immu- cinogen-macromolecular adducts has made it possible to mea noaffmily chromalography and HPLC have been used lo delecl sure adducts in blood and tissue samples (293-295). Although Ihese alkyl adducts in placenta! DNA (321, 324). The power of hemoglobin and albumin are not considered targets for the HPLC combined with the "P-posllabeling assay is evidenl pathobiological effects of carcinogens, these macromolecules because O6-elhyldeoxyguanosine and /V7-methyldeoxyguano- have certain advantages for the molecular dosimetry of expo sine adducts can be detected with a high degree of sensitivity sure to carcinogens. For example, RBC have a lifetime of about and specificily in lung lissues al the level of 1 adduci in IO7 120 days in humans, so the levels of carcinogen-hemoglobin nucleotides (325, 326). adducts may be an integrative measure of exposure during a The wide range in the amounts of carcinogen-macromolecu- period of nearly 4 months. In addition, these protein adducts, lar adducls measured in ihe sludies discussed above is in pari a unlike DNA adducts, are not considered to be repaired in the reflection of occupational, environmenl, or life-style exposure circulating RBC, and mg quantities of hemoglobin can be lo chemical carcinogens. Inlerindividual differences in ihe bal obtained from a few ml of blood. Ehrenberg et al. (296) pi ance belween metabolic activation and deactivation of chemical oneered this area of research by measuring alkylating agents carcinogens and in DNA repair rates are also likely to conlrib- such as ethylene oxide bound to hemoglobin. The amounts of ute to the variation. ethylene oxide-hemoglobin and 4-aminobiphenyl-hemoglobin Although methods to measure carcinogen-macromolecular adducts are substantially increased in tobacco smokers com adducts are an importanl conlribulion to improved carcinogen pared to nonsmokers (297, 298), and the 4-aminobiphenyl- exposure assessment, carcinogen-macromolecular adducls will hemoglobin adducts levels decrease upon smoking cessation noi be a precise quanlitative predictor of cancer risk because of (299). The kinetics of adduci loss mirrors the 120-day half-life the multistage and complex nalure of human carcinogenesis. of the erythrocytes. Occupational exposure lo elhylene oxide has also been monilored (300). Dietary exposure to chemical In biology, one rarely deals with classes of identical entities, but carcinogens can be monitored by measuring carcinogen-albu nearly always studies populations consisting of unique individuals. This is true for every level of hierarchy, from cells to ecosystems. min adducts. Wild et al. (301) have found thai exposure to aflaloxin B, in coniaminaled grain products is widespread in The Growth of Biological Thought The Gambia and Senegal, >95% of the subjects had deteclable Ernst Mayr, 1982 aflatoxin-albumin adducts, and the interindividual variation even within a single village can be 100-fold. Carcinogen-DNA adducts have also been measured in work Cancer Risk Assessment Perspective ers exposed to chemical carcinogens usually in complex mix Quantitative risk assessment is currenlly more mathematical tures such as coke oven exhaust. For example, PAH-DNA extrapolation and scientific inluition than a rigorous science. adducts in peripheral blood lymphocytes have been measured However, the stalus of cancer risk assessmenl should improve by enzyme immunoassays in coke oven workers, foundry work during the 1990s. This optimism is based largely on the recent ers, roofers, and fire fighters (302-307). In the occupationally advances that have increased our understanding of the molec exposed individuals, enzyme immunoassays detecled 1 to 1200 ular mechanisms of human disease palhogenesis. The discovery adducts (BPDE-DNA aniigenic equivalent) per IO8 unmodi of multiple genetic and epigenelic changes during carcinogen fied nucleolides in 25 to 100% of the subjects (303-305, 307- esis is an example lhal provides opporlunilies for bolh early 309). These adducts have also been detected by complementary diagnosis of preneoplaslic lesions and novel interventive meth methods in placenta! DNA samples in levels that ranged be ods to inhibit or reverse carcinogenesis. These advances are tween 10 and 500 in 10s nucleotides. In this case, synchronous driven in pari by improved biotechnology. For example, polym- scanning fluorimetry and gas chromalography-mass spectros- erase chain reaction coupled wilh direcl DNA sequencing al copy have given consistent results (310-315). lows the detection of mutalions in formalin-fixed, paraffin- A comparison between deteclion methods and end poinls has embedded tissue sections and the "retrospective epidemiologi- 5035s

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5044s

Curtis C. Harris

Cancer Res 1991;51:5023s-5044s.

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