Significance of Genetic Polymorphisms in Cancer Susceptibility

  • Eino Hietanen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 472)


The variability of biotransformation enzyme activities is associated with various types of exposures and host factors, possibly originating from early childhood. Since many carcinogenic compounds require metabolic activation before being capable of reacting with cellular macromolecules, individual features of carcinogen metabolism may play an essential role in the development of environmental cancer.1 As individual response to environmental mutagens and carcinogens vary there is no pure distinction between purely genetic or environmental cancers. Often there is no incompatibility between environmental and genetic origin of cancer as is the case e.g. with smoking where a chemical mixture induces cancer but individuals show different sensitivity to these agents causing a cancer. A complicating factor is the multistage etiology of carcinogenesis implying the involvement of many distinct events. However, it has become evident that the enzymes activating and inactivating exogenous carcinogens are involved.


Cancer Susceptibility Lung Cancer Risk Bladder Cancer Risk GSTM1 Null Genotype CYP2D6 Gene 
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  1. 1.
    Raunio, H., Husgafvel-Pursiainen, K., Anttila, S., Hietanen, E., Hirvonen, A., and Pelkonen, O. Diagnosis of polymorphisms in carcinogen-activaitng and inactivating enzymes and cancer susceptibility-a review. Gene 159: 113–121 (1995).PubMedCrossRefGoogle Scholar
  2. 2.
    Swift, M., Morrell, D., Massey, R.B., and Chase, C.L. Incidence of cancer in 161 families affected by ataxia-teleangiectasia. N. Engl. J. Med. 325: 1831–1836 (1991).PubMedCrossRefGoogle Scholar
  3. 3.
    Vainio, H. Biomarkers in metabolic subtyping-Relevance for environmental cancer control. Arch. Toxicol. (Suppl. 20 ): 303–310 (1998).CrossRefGoogle Scholar
  4. 4.
    Kleihues, P., Schauble, B., zur Hausen, A., Esteve, J., and Ohkagi, H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am. J. Pathol. 150: 1–13 (1997).PubMedGoogle Scholar
  5. 5.
    Li, F.P. The 4`h American Cancer Society Award for Research Excellence in Cancer Epidemiology and Prevention. Phenotypes, genotypes, and interventions for hereditary cancers. Cancer Epidem. Biomarkers Prey. 4: 579–582 (1995).Google Scholar
  6. 6.
    Malkin, D., Jolly, K.W., Barbier, N., Look, A.T., Friend, S.H., Gebhardt, M.C., Andersen, T.L., Borresen, A.L., Li, F.P., Garber, J., and al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N. Engl. J. Med. 326: 1309–1315 (1992).PubMedCrossRefGoogle Scholar
  7. 7.
    Nebert, D.W., McKinnon, R.A., and Puga, A. Human drug-metabolizing enzyme polymorphisms: effects on risk of toxicity and cancer. DNA Cell Biol. 15: 273–280 (1996).PubMedCrossRefGoogle Scholar
  8. 8.
    Gooderham, N.J., Murray, S., Lynch, A.M., Edwards, R.J., Yadollahi-Farsani, M., Bratt, C., Rich, K.J., Zhao, K., Murray, B.P., Bhadresa, S., Crosbie, S.J., Boobis, A.R., and Davies, D.S. Heterocyclic amines: evaluation of their role in dietassociated human cancer. Br. J. Clin. Pharmacol. 42: 91–98 (1996).PubMedCrossRefGoogle Scholar
  9. 9.
    Catteau, A., Bechtel, Y.C., Poisson, N., Bechtel, P.R., and Bonaiti-Pellie, C. A population and family study of CYP1A2 using caffeine urinary metabolites. Eur. J. Clin. Pharmacol. 47: 423–430 (1995).PubMedCrossRefGoogle Scholar
  10. 10.
    Kadlubar, F.F. Biochemical individuality and its implications for drug and carcinogen metabolism: Recent insights from acetyltransferase and cytochrome P4501A2 phenotyping and genotyping in humans. Drug. Metab. Disp. 26: 37–46 (1994).Google Scholar
  11. 11.
    MacLeod, S.L., Tang, Y.-M., Yokoi, T., Kamataki, T., Doublin, S., Lawson, B., Massengill, J., Kadlubar, F.F., and Lang, N.P. The role of recently discovered genetic polymorphism in the regulation of the human CYP1A2 gene. Proc. Amer Assoc. Cancer. Res. 396:•• (1998).Google Scholar
  12. 12.
    Tang, B.K., Zubovits, T., and Kalow, W. Determination of acetylated caffeine metabolites by high-performance exclusion chromatography. J. Chromatogr. 375: 170–173 (1986).CrossRefGoogle Scholar
  13. 13.
    Buters, J.T.M., Tang, B.-K., Pineau, T., Gelboin, H.V., Kimura, S., and Gonzalez, F.J. Role of CYP1A2 in caffeine pharmacokinetics and metabolism: studies using mice deficient in CYP1A2. Pharmacokinetics 6: 291–296 (1996).CrossRefGoogle Scholar
  14. 14.
    Petersen, D.D., McKinney, C.E., Ikeya, K., Smith, H.H., Bale, A.E., McBride, O.W., and Nebert, D.W. Human CYP1A1 gene: cosegregation of the enzyme inducibility phenotype and an RFLP. Am. J. Hum. Genet. 48: 720–725 (1990).Google Scholar
  15. 15.
    Wedlund, P.J., Kimura, S., Gonzales, EJ., and Nebert, D.W. 1462 mutation in the human CYP1A1 allele gene: lack of correlation with either the MspI 1.9 kb (M2) allele or CYP1A1 inducibility in a three-generation family of East Mediterraean descent. Pharmacogenetics 4: 21–26 (1994).PubMedCrossRefGoogle Scholar
  16. 16.
    Crofts, F, Taioli, E., Trachman, J., Cosma, G.N., Currie, D., Toniolo, P., and Garte, S.J. Functional significance of different human CYP1A1 genotype, mRNA expression, and enzymatic activity in humans. Pharmacokinetics 4: 242–246 (1994).Google Scholar
  17. 17.
    Landi, M.T., Bertazzi, EA., Shields, P.G., Clark, G., Lucier, G.W., Garte, S.J., Cosma, G., and Caporaso, N.E. Association between CYP1A1 genotype, mRNA expression and enzymatic activity in humans. Pharmacokinetics 4: 242–246 (1994).CrossRefGoogle Scholar
  18. 18.
    Kawajiri, K., Nakachi, K., Imai, K., Yoshii, A., Shinoda, N., and Watanabe, J. Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P4501A1 gene. FEBS Lett. 263: 131–133 (1990).PubMedCrossRefGoogle Scholar
  19. 19.
    Nakachi, K., Imai, K., Hayashi, S., Watanabe, S., and Kawajiri, K. Genetic susceptibility of squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Res. 51: 5177–5189 (1991).PubMedGoogle Scholar
  20. 20.
    Hayashi, S.I., Watanabe, J., Nakachi, K., and Kawajiri, K. Genetic linkage of lung cancer-associated MspI polymorhisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene. J. Biochem. 110: 407–411 (1991).PubMedGoogle Scholar
  21. 21.
    Shields, P.G., Sugimura, H., Caporaso, N.E., Petruzzelli, S.F., Bowman, E.D., Trump, B.F., Weston, A., and Harris, C.C. Polycyclic aromatic hydrocarbon-DNA adducts and the CYP1A1 restriction fragment length polymorphism. Environ. Health Perspect. 98: 191–194 (1992).PubMedCrossRefGoogle Scholar
  22. 22.
    Tefre, T., Ryberg, D., Haugen, A., Nebert, D.W., Skaug, V., Brogger, A., and Borresen, A L. Human CYP1A1 (cytochrome P1450) gene: lack of association between the MspI restriction fragment length polymorphism and incidence of lung cancer in a Norwegian population. Pharmacogenetics 1: 20–25 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    Hirvonen, A., Husgafvel-Pursiainen, K., Karjalainen, A., Anttila, S., and Vainio, H. Point-mutational MspI and Ile-Val polymorphisms closely linked in the CYP1A1 gene: Lack of association with susceptibility to lung cancer in a Finnish Study population. Cancer Epidem. Biomarkers Prevention 1: 485–489 (1992).Google Scholar
  24. 24.
    Nakachi, K., Imai, K., Hayashi, S., and Kawajiri, K. Polymorphisms of the CYP1A1 and glutathione S-transferase genes associated with susceptibility to lung cancer in relation to cigarette dose in a Japanese population. Cancer Res. 53: 2994–2999 (1993).PubMedGoogle Scholar
  25. 25.
    Okada, T., Kawashima, K., Fukushi, S., Minakuchi, T., and Nishimura, S. Association between a cytochrome P450 CYP1A1 genotype and incidence of lung cancer. Pharmacogenetics 4: 333–340 (1994).PubMedCrossRefGoogle Scholar
  26. 26.
    Lang, N.P., Butler, M.A., Massengill, J., Lawson, M., Stotts, R.C., Hauer-jensen, M., and Kadlubar, F.F. Rapid metabolic phenotypes for acetyltransferase and cytochrome P4501A2 and putative exposure to food-borne heterocyclic amines increase the risk for colorectal cancer or polyps. Cancer Epidemiol. Biomarkers & Prev. 3: 675–682 (1994).Google Scholar
  27. 27.
    London, S.J., Daly, A.K., Thomas, D.C., Caporaso, N.E., and Idle, J.R. Methodological issues in the interpretation of studies of the CYP2D6 genotype in relation to lung cancer risk. Pharmacogenetics 4: 107–108 (1994).PubMedCrossRefGoogle Scholar
  28. 28.
    Caporaso, N.E., Tucker, M.A., Hoover, R.N., Hayes, R.B., Pickle, L.W., Issaq, H.J., Muschik, G.M., Green-Gallo, L., Buivys, D., Aisner, S., Resau, J.H., Trump, B.E, Tollerud, D., Weston, A., and Harris, C.C. Lung cancer and the debrisoquine metabolic phenotype. J. Natl. Cancer Inst. 82: 1264–1272 (1990).PubMedCrossRefGoogle Scholar
  29. 29.
    Stucker, I., Cosme, J., Laurent, Ph., Cenée, S., Beaune, Ph., Bignon, J., Depierre, A., Milleron, B., and Hémon, D. CYP2D6 genotype and lung cancer risk according to histologic type and tobacco exposure. Carcinogenesis 16: 2759–2764 (1995).PubMedCrossRefGoogle Scholar
  30. 30.
    Bouchardy, C., Benhamou, S., and Dayer, P. The effect of tobacco on lung cancer risk depends on CYP2D6 activity. Cancer. Res. 56: 251–253 (1996).PubMedGoogle Scholar
  31. 31.
    Wynder, E.L. and Hoffmann, D. Smoking and lung cancer: scientific challenges and opprotunities. Cancer Res. 54: 5284–5295 (1994).PubMedGoogle Scholar
  32. 32.
    Agundez, J.A.G., Ledesma, M.C., Benitez, J., Ladero, J.M., Rodriguez-Lescure, A., Diaz-Rubio, E., and Diaz-Rubio, M. CYP2D6 genes and risk of liver cancer. Lancet 345: 830–831 (1995).PubMedCrossRefGoogle Scholar
  33. 33.
    Yu, M.-W., Gladek-Yarborough, A., Chiamprasert, S., Santella, R.M., Liaw, Y.-E, and Chen, C.-J. Cytochrome P450 2E1 and glutathione S-transferase Ml polymorphisms and susceptibility to hepatocelluar carcinoma. Gastroenterology 109: 1266–1273 (1995).PubMedCrossRefGoogle Scholar
  34. 34.
    Tsutsumi, M., Takada, A., and Wang, J.-S. Genetic polymorphisms of cytochrome P4502E1 related to the development of alcoholic liver disease. Gastroenterology 107: 1430–1435 (1994).PubMedGoogle Scholar
  35. 35.
    Brockmöller, J., Kerb, R., Drakoulis, N., Nitz, M., and Roots, I. Genotype and phenotype of glutathione S-transferase class m isoenzymes m and y in lung cancer patients and controls. Cancer Res. 53: 1004–1011 (1993).PubMedGoogle Scholar
  36. 36.
    Hirvonen, A., Husgafvel-Pursiainen, K., Anttila, S., and Vainio, H. The GSTM1 null genotype as a potential risk modifier for squamous cell carcinoma of the lung. Carcinogenesis 14: 1479–1481 (1993).PubMedCrossRefGoogle Scholar
  37. 37.
    Zhong, S., Howie, A.E, Ketterer, B., Taylor, J., Hayes, J.D., Beckett, G.J., Wathen, C.G., Wolf, C.R., and Spurr, N.K. Glutathione S-transferase m locus: use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis 12: 1533–1537 (1991).PubMedCrossRefGoogle Scholar
  38. 38.
    Kihara, M., Kihara, M., and Noda, K. Lung cancer risk of GSTM1 null genotype is dependent on the extent of tobacco smoke exposure. Carcinogenesis 15: 415–418 (1994).PubMedCrossRefGoogle Scholar
  39. 39.
    Bell, D.A., Taylor, J.A., Paulson, D.F., Robertson, C.N., Mohler, J.L., and Lucier, G.W. Genetic risk and carcinogen exposure: a common inherited defect of the carcinogen-metabolism gene glutathione S-transferase M1 (GSTM1) that increases susceptibility to bladder cancer. J. Natl. Cancer Inst. 85: 1159–1164 (1993).PubMedCrossRefGoogle Scholar
  40. 40.
    Brockmöller, J., Kerb, R., Drakoulis, N., Staffeldt, B., and Roots, I. Glutathione S-transferase Ml and its variants A and B as host factors of bladder cancer susceptibility: A case-control study. Cancer Res. 54: 4103–4111 (1994).Google Scholar
  41. 41.
    Ilett, K.E, David, B., Dethcon, P., Castleden, W, and Kwa, R. Acetylator phenotype in colorectal carcinoma. Cancer Res. 47: 1466–1469 (1991).Google Scholar
  42. 42.
    Bell, D.A., Stephens, E.A., Castranio,T., Umbach, D.M., Watson, M., Deakin, M., Elder, M., Henrickse, C., Duncan, H., and Strange, R.C. Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer. Cancer Res. 55: 3537–3542 (1995).Google Scholar
  43. 43.
    Bartsch, H. and Hietanen, E. The role of individual susceptibility in cancer burden related to environmental exposure. Environ. Health Perspect. 104 (Suppl 3): 569–577 (1996).PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Eino Hietanen
    • 1
  1. 1.Department of Clinical PhysiologyTurku University HospitalTurkuFinland

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