Abstract
The characterization of genetic determinants for cancer susceptibility is important for understanding disease pathogenesis and for preventive measures. There is growing evidence that a group of predisposing polymorphic genes exists, such as those involved in carcinogen metabolism and repair, which may increase cancer in certain environmentally exposed subjects, even those exposed only to low levels of carcinogens. In developing preventive strategies, it is therefore necessary to identify these vulnerable members in our society, particularly those suffering from an unfortunate combination of high carcinogen exposure, cancer-predisposing genes and lack of protective (dietary) factors. Thus, molecular epidemiology faces the difficult task of analyzing carcinogen-exposed individuals for a combination of genotypes associated with cancer susceptibility. Once identified, combinations of cancer-predisposing genes can then be used as intermediate risk markers rather than taking cancer as an endpoint. In case-control studies, simultaneous measurements were carried out in each subject to determine exposure/early effect markers, e.g. polycyclic aromatic hydrocarbons (PAH)-DNA adducts, and susceptibility markers, e.g. genetic polymorphism, in drug-metabolizing enzymes related to cytochrome P450 1A1 (CYP1A1) and glutathione S-transferase (GSTM1) genes. The genotype dependence of human lung (+)-antibenzo[a]pyrene diol-epoxide (BPDE)-DNA adducts in lung cancer patients was examined. BPDE-DNA adduct levels in bronchial tissue of smokers with high pulmonary CYP1A1 inducibility (by immunohistochemistry) and GSTM1 inactive were ~100-fold higher than in subjects with an active GSTM1 at similar smoking dose. Further genetic analyses confirmed that the combination of CYP1A1 homozygous mutants and GSTM1 inactive leads to high levels of BPDE-DNA adducts in human lung of smokers and white blood cells of PAH-exposed coke oven workers. Thus, BPDE-DNA adduct levels resulting from the “at risk” genotype combinations may serve as markers to identify high-risk subjects among smokers and individuals occupationally and/or environmentally exposed to PAH.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Alexandrie AK, Sundberg MI, Seidegard J, Tornling G, Ranung A (1994) Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. Carcinogenesis 15: 1785–1790
Alexandrov K, Rojas M, Geneste O, Castegnaro M, Camus AM, Petruzzelli S, Giuntini C, Bartsch H (1992) An improved fluorometric assay for dosimetry of benzo[a]pyrene diolepoxide-DNA adducts in smoker’s lung: comparison with total bulky adducts and aryl hydrocarbon hydroxylase activity. Cancer Res 52: 6248–6253
Bartsch H (1996) DNA adducts in human carcinogenesis: etiological relevance and structureactivity relationship. Mutat Res 40: 67–79
Bartsch H, Hietanen E (1996) The role of individual susceptibility in cancer burden related to environmental exposure. Environ Health Perspect 104 (Suppl 3): 569–577
Bartsch H, Hietanen E, Petruzzelli S, Giuntini C, Saracci R, Mussi A, Angeletti CA (1990) Possible prognostic value of pulmonary Ah-locus-linked enzymes in patients with tobacco-related lung cancer. Int J Cancer 46: 185–188
Bartsch H, Rojas M, Alexandrov K, Camus A-M, Castegnaro M, Malaveille C, Anttila S, Hirvonen K, Husgafvel-Pursiainen K, Hietanen E, Vainio H (1995) Metabolic polymorphism effecting DNA binding and excretion of carcinogens in humans. Pharmacogenetics 5: S84 - S90
Brockmöller J, Kerb R, Drakoulis N, Nitz M, Roots I (1993) Genotype and phenotype of glutathione S-transferase class isoenzymes in lung cancer patients and controls. Cancer Res 53: 1004–1011
Caporaso N, Goldstein A (1995) Cancer genes: single and susceptibility: exposing the difference. Pharmacogenetics 5: 59–63
Cascorbi I, Brockmöller J, Roots I (1996) A C4887A polymorphism in exon 7 of human CYPIA1: population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res 56: 4965–4969
Denissenko MF, Pao A, Tang MS, Pfeifer GP (1996) Preferential formation of ben- zo[a]pyrene adducts at lung cancer mutational hotspots in p53. Science 274: 430–432
Goto M, Yoneda S, Yamamoto M, Kawajiri K (1996) Prognostic significance of germ line polymorphisms of the CYP1A1 and glutathione S-transferase genes in patients with non-small cell lung cancer. Cancer Res 6: 3725–3730
Hayashi SI, Watanabe J, Kawajiri K (1992) High susceptibility to lung cancer analyzed in terms of combined genotypes of P4501A1 and Mu-class glutathione S-transferase genes. Jpn J Cancer Res 83: 866–870
Hsu TC (1987) Genetic predisposition to cancer with special reference to mutagen sensitivity. In vitro Cellular and Developmental Biology 23: 591–603
Kawajiri K, Nakachi K, Imai K, Yoshii A, Shinoda N, Watanabe J (1990) Identification of genetically high risk individuals to lung cancer by DNA polymorphism of the cytochrome P4501A1 gene. FEBS Lett 263: 131–133
Kihara M, Kihara M, Noda K (1995) Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorph-isms in a Japanese population. Carcinogenesis 16: 2331–2336
McWilliams JE, Sanderson BJS, Harris EL, Richert-Boe KE, Henner WD (1995) Glutathione S-transferase M1 (GSTM1) deficiency and lung cancer risk. Cancer Epidemiol Biomarkers Prey 4: 589–594
Nakachi K, Imai K, Hayashi S-I, Watanabe J, Kawajiri K (1991) Genetic susceptibility to squamous cell carcinoma of the lung in relation to cigarette smoking dose. Cancer Res 51: 5177–5180
Nakachi K, Imai K, Hayashi S-I, Kawajiri K (1993) 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
Nakajima T, Elovaara E, Anttila S, Hirvonen A, Camus A-M, Hayes JD, Ketterer B, Vainio H (1995) Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. Carcinogenesis 16: 707–711
Rojas M, Alexandrov K, van Schooten F-J, Hillebrand M, Kriek E, Bartsch H (1994) Validation of a new fluorometric assay for benzo[a]pyrene diolepoxide-DNA adducts in human white blood cells: comparison with 32P-postlabeling and ELISA. Carcinogenesis 15: 557–560
Rojas M, Alexandrov K, Auburtin G, Wastiaux-Denamur A, Mayer L, Mahieu B, Sebastien P, Bartsch H (1995) Anti-benzo[a]pyrene diolepoxide-DNA adduct levels in peripheral mononuclear cells from coke oven workers and the enhancing effect of smoking. Carcinogenesis 6: 1373–1376
Rojas M, Alexandrov K, Cascorbi I, Brockmöller J, Likhachev A, Pozharisski K, Bouvier G, Auburtin G, Mayer L, Koop-Schneider A, Roots I, Bartsch H (1998) High benzo[a]pyrene diol-epoxide DNA adduct levels in lung and blood cells from subjects with combined CYP1A1 MspI/MspI-GSTM1*0/*0 genotypes. Pharmacogenetics 8: 109–118
Ryberg D, Kure E, Lystad S, Skaug V, Stangeland L, Mercy I, Bi rresen A-L, Haugen A (1994) p53 mutations in lung tumors: relationship to putative susceptibility markers for cancer. Cancer Res 54: 1551–1555
Tang D, Santella RM, Blackwood AM, Young T-L, Mayer J, Jaretzki A, Grantham S, Tsai W-Y, Perera FP (1995) A molecular epidemiological case-control study of lung cancer. Cancer Epidemiol Biomarkers Prey 4: 341–346
Van Schooten FJ, Jongeneelen FJ, Hillebrand MJX, van Leeuwen FE, de Loof AJA, Dijkmans APG, van Rooij JGM, den Engelse L, Kriek E (1995) Polycyclic aromatic hydrocarbon-DNA adducts in white blood cell DNA and 1-hydroxypyrene in the urine from aluminum workers: relation with job category and synergistic effect of smoking. Cancer Epidemiol Biomarkers Prey 4: 69–77
Vaury C, Laine R, Noguiez P, de Coppet P, Jaulin C, Praz F, Pompon D, Amor-Guéret M (1995) Human glutathione S-transferase M1 null genotype is associated with a high inducibility of cytochrome P450 1A1 gene transcription. Cancer Res 55: 5520–5523
Vineis P (1997) Molecular epidemiology: low-dose carcinogens and genetic susceptibility. Int J Cancer 71: 1–3
Vineis P, Bartsch H, Caporaso N, Harrington AM, Kadlubar FF, Landi MT, Malaveille C, Shields PG, Skipper P, Talaska G, Tannenbaum SR (1994) Genetically based N-acetyltransferase metabolic polymorphism and low-level environmental exposure to carcinogens. Nature 369: 154–156
Wiencke JK, Kelsey KT, Varkonyi A, Semey K, Wain JC, Mark E, Christiani DC (1995) Correlation of DNA adducts in blood mononuclear cells with tobacco carcinogen-induced damage in human lung. Cancer Res 55: 4910–4914
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1998 Springer-Verlag Berlin · Heidelberg
About this paper
Cite this paper
Bartsch, H., Rojas, M., Alexandrov, K., Risch, A. (1998). Impact of Adduct Determination on the Assessment of Cancer Susceptibility. In: Schwab, M., Rabes, H.M., Munk, K., Hofschneider, H.P. (eds) Genes and Environment in Cancer. Recent Results in Cancer Research, vol 154. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-46870-4_5
Download citation
DOI: https://doi.org/10.1007/978-3-642-46870-4_5
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-642-46872-8
Online ISBN: 978-3-642-46870-4
eBook Packages: Springer Book Archive