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Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility

  • Original Article – Cancer Research
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Abstract

Objectives

Tobacco exposure remains the main etiologic factor for lung cancer (LC). Interactions between environment and individual genetic profile are particularly important for this disease. The aim of this study was to evaluate the contribution of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 polymorphisms for the susceptibility to LC in a Portuguese population considering their demographic and clinical characteristics.

Materials and methods

A total of 200 LC and 247 controls subjects from the Centre of Portugal were studied. Clinical and demographic characteristics were collected from clinical files and by individual questionnaires. Polymorphisms of CYP1A1*2A, CYP1A1*2C, CYP2D6*4, GSTP1, GSTM1, GSTT1 and NAT2 were genotyped using PCR–RFLP, PCR multiplex, ARMS and real time.

Results

Gender, family history of cancer, smoke cessation and alcohol consumption were independent risk factors (p < 0.05). Associations found between phases I and II genes and LC population reveal a sex dependent distribution. Logistic regression analysis demonstrates that enhanced activation by CYPs, associated by reduced or loss of function of phase II enzymes, can lead to a greater risk. GSTP1 and NAT2 polymorphisms studied have a significant contribution for the histological tumour types and the presence of metastases, at time of diagnosis, respectively, when males with smoking habits were considered.

Conclusion

Multiple interactions between environment and individual characteristics are clearly associated to this disease. Variants of the detoxification genes may act synergistically contributing to this disease and modifying the risk posed by smoking and sex. The GSTT1*0 and GSTP1 (Ile462Val) might contribute to the malignant phenotype through different mechanisms.

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References

  • Benedetti A, Parent ME, Siemiatycki J (2006) Consumption of alcoholic beverages and risk of lung cancer: results from two case-control studies in Montreal, Canada. Cancer Causes Control 17:469–480

    Article  PubMed  Google Scholar 

  • Bertram J, Rogers A (1981) Recovery of bronchial epithelium on stopping smoking. Br Med J 283:1567–1569

    Article  CAS  Google Scholar 

  • Board P, Menon D (2013) Glutathione transferases, regulators of cellular metabolism and physiology. Biochim Biophys Acta 1830:3267–3288

    Article  CAS  PubMed  Google Scholar 

  • Borlak J, Reamon-Buettner S (2006) N.Acetyltransferases 2 (NAT2) gene polymorphisms in colon and lung cancer patients. BMC Med Genet 7:58. doi:10.1186/1471-2350-7-58

    Article  PubMed Central  PubMed  Google Scholar 

  • Božina N, Bradamante V, Lovrić M (2009) Genetic polymorphism of metabolic enzymes P450 (CYP) as a susceptibility factor for drug response, toxicity, and cancer risk. Arh Hig Rada Toksikol 60:217–242

    PubMed  Google Scholar 

  • Carlsten C, Saggo GS, Frodshem AJ, Burke W, Higgins JP (2008) Glutathione S-Transferase M1 (GSTM1) polymorphisms and lung cancer: a literature-based systematic HuGE review and meta-analysis. Am J Epidemiol 167:759–774

    Article  CAS  PubMed  Google Scholar 

  • Chen Z, Li Z, Niu X, Yu Y, Lu S (2011) The effect of CYP1A1 polymorphism on the risk of lung cancer: a global meta-analysis based on 71 case-control studies. Mutagenesis 26:437–446

    Article  CAS  PubMed  Google Scholar 

  • Christensen PM, Gotzsche PC, Brosen K (1997) The sparteine/debrisoquine (CYP2D6) oxidation polymorphism and the risk of lung cancer: a meta-analysis. Eur J Clin Pharmacol 51:389–393

    Article  CAS  PubMed  Google Scholar 

  • Cohen S, Paré P, Man S, Sin D (2007) The growing burden of chronic obstructive pulmonary disease and lung cancer in women. Am J Respir Crit Care Med 176:113–120

    Article  CAS  Google Scholar 

  • Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, Comber H, Forman D, Bray F (2013) Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer 49:1374–1403

    Article  CAS  PubMed  Google Scholar 

  • Freudenheim JL, Ritz J, Smith-Warner SA, Albanes D, Bandera EV, van den Brandt P, Colditz G, Feskanich D, Goldbohm RA, Harnack L, Miller A, Rimm E, Rohan T, Sellers T, Virtamo J, Willett W, Hunter D (2005) Alcohol consumption and risk of lung cancer: a pooled analysis of cohort studies. Am J Clin Nutr 82:657–667

    CAS  PubMed  Google Scholar 

  • Gao CM, Takezaki T, Wu JZ, Li ZY, Liu YT, Li SP et al (2002) Glutathione S-Transferase M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case control study of a high incidence area in Jiangsu Province, China. Cancer Lett 188:95–102

    Article  CAS  PubMed  Google Scholar 

  • Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbeum M, Wolf CR (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Reprinted from Nature, Macmillan Magazines Ltd 347:773–776

    CAS  Google Scholar 

  • Gross M, Kruisselbrink T, Anderson K, Lang N, McGovern P, Delongchamp R, Kadlubar F (1999) Distribution and concordance of N-acetyltransferase genotype and phenotype in an American population. Cancer Epidemiol Biomark Prev 8:683–692

    CAS  Google Scholar 

  • Hayashi S, Watanabe J, Nakachi K, Kawajiri K (1991) Genetic linkage of lung cancer –associated Msp1 polymorphism with aminoacid replacement in the heme binding region of the human cytochrome P450 1A1 gene. J Biochem 110:407–411

    CAS  PubMed  Google Scholar 

  • Hayes J, Strange R (2000a) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61:154–166

    Article  CAS  PubMed  Google Scholar 

  • Hayes J, Strange R (2000b) Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology 61:154–166

    Article  CAS  PubMed  Google Scholar 

  • Hecht SS (2002) Cigarette smoking and lung cancer: chemical mechanisms and approaches to prevention. Lancet oncol 3:461–469

    Article  CAS  PubMed  Google Scholar 

  • Holley S, Fryer A, Haycock J, Grubb A, Strange R, Hoban P (2007) Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis. Carcinogenesis 28(11):2268–2273

    Article  CAS  PubMed  Google Scholar 

  • Josephy P (2010) Genetic variations in human glutathione transferase enzymes: significance for pharmacology and toxicology. Hum Genomics Proteomics 2010:876940

  • Kawajiri K, Nakachi K, Imai K et al (1990a) Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P450 1A1 gene. FEBS Lett 263:131–133

    Article  CAS  PubMed  Google Scholar 

  • Kawajiri K, Nakachi K, Imai K et al (1990b) Identification of genetically high risk individuals to lung cancer by DNA polymorphisms of the cytochrome P4501A1 gene. FEBS Lett 263:131–133

    Article  CAS  PubMed  Google Scholar 

  • Kawajiri K, Nakachi K, Imai K, Watanabe J, Hayashi S (1993) The CYP1A1 gene and cancer susceptibility. Crit Rev Oncol Hematol 14:77–87

    Article  CAS  PubMed  Google Scholar 

  • Nakachi K, Imai K, Hayashi S, 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

    CAS  PubMed  Google Scholar 

  • North C, Christiani D (2013) Women and lung cancer: what is new? Semin Thorac Surg 25:87–94

    Article  Google Scholar 

  • Pallis A, Syrigos K (2013) Lung cancer in never smokers: disease characteristics and risk factors. Crit Rev Oncol/Hematol 88:494–503

    Article  Google Scholar 

  • Parsons A, Daley A, Begh R, Aveyard P (2010) Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis. Systematic review of observational studies with meta-analysis. BMJ 340:b5569. doi:10.1136/bmj.b5569

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Pool-Zobel B, Veeriah S, Böhmer FD (2005) Modulation of xenobiotic metabolizing enzymes by anticarcinogens—focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat Res 591(1–2):74–92

    Article  CAS  PubMed  Google Scholar 

  • Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S (2013) Polymorphic cytochrome P450 enzymes (Cyps) and their role in personalized therapy. PLoS ONE 8(12):e82562. doi:10.1371/journal.pone.0082562

    Article  PubMed Central  PubMed  Google Scholar 

  • Ritchie K, Henderson C, Wang X, Vassieva O, Carrie D et al (2007) Glutathione transferase plays a critical role in the development of lung carcinogenesis following exposure to tobacco-related carcinogens and urethane. Cancer Res 67:9248–9257

  • Rostami-Hodjegan A, Lennard MS, Woods HF, Tucker GT (1998) Meta-analysis of studies of the CYP2D6 polymorphism in relation to lung cancer and Parkinson’s disease. Pharmacogenetics 8:227–238

    Article  CAS  PubMed  Google Scholar 

  • Saxena A, Dhillon VS, Shahid M, Khalil HS et al (2012) GSTP1 methylation and polymorphism increase the risk of breast cancer and the effects of diet and lifestyle in breast cancer patients. Exp Ther Med 4(6):1097–1103 PMCID: PMC3494109

    PubMed Central  CAS  PubMed  Google Scholar 

  • Seyfried T, Shelton L (2010) Cancer as a metabolic disease. Nutr Metab 7:7

    Article  Google Scholar 

  • Siegfried JM (2001) Women and lung cancer: does oestrogen play a role? Lancet Oncol 2:506–513

    Article  CAS  PubMed  Google Scholar 

  • Smith C, Wadelius M, Gough A, Harrisson D, Wolf C, Rane A (1997) A simplified assay for the arylamine N-acetyltransferase 2 polymorphism validated by phenotyping with isoniazid. J Med Genet 34:758–760

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sreejal Syamola V, Hariharan S et al (2005) Possible risk modification by CYP1A1, GSTM1 and GSTT1 gene polymorphisms in lung cancer susceptibility in a South Indian population. J Hum Genet 50:618–627

    Article  Google Scholar 

  • Sweeney C, Nazar-Stewart V, Stapleton P, Eaton D, Vaughan T (2003) Glutathione S-transferase M1, T1 and P1 polymorphisms and survival among lung cancer patients. Cancer Epidemiol Biomark Prev 12:527–533

    CAS  Google Scholar 

  • Tyczynski J, Bray F, Parkin DM (2003) Lung cancer in Europe in 2000: epidemiology, prevention and early detection. Lancet oncol 4:45–55

    Article  PubMed  Google Scholar 

  • Wright CM, Larsen JE, Colosimo ML, Barr JJ, Chen L, McLachlan RE, Yang IA, Bowman RV, Fong KM (2010) Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in non small cell lung cancer. Eur Respir J 35:152–159

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Sin D (2011) Improved patient outcome with smoking cessation: when is it too late? Int J COPD 6:259–267

    Google Scholar 

  • Zanger U, Schwab M (2013) Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities and impact of genetic variation. Pharmacol Ther 138:103–141

    Article  CAS  PubMed  Google Scholar 

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Mota, P., Silva, H.C., Soares, M.J. et al. Genetic polymorphisms of phase I and phase II metabolic enzymes as modulators of lung cancer susceptibility. J Cancer Res Clin Oncol 141, 851–860 (2015). https://doi.org/10.1007/s00432-014-1868-z

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  • DOI: https://doi.org/10.1007/s00432-014-1868-z

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