Abstract
Purpose: Polycyclic aromatic hydrocarbons are activated by cytochrome P450 1A1 (CYP1A1) and inactivated by glutathione S-transferase mu (GSTM1). Therefore, it is expected that a combination of proficient CYP1A1 genotype with deficient GSTM1 variant would result in particularly elevated lung cancer (LC) risk, especially for squamous cell carcinoma (SCC). This study was aimed to validate whether the CYP1A1-C 3801 (CYP1A1*2) allele has an unfavorable significance alone and/or in combination with the GSTM1 deficiency. Methods: We compared the distribution of CYP1A1 and GSTM1 genotypes in LC patients (n=141), healthy donors (HD, n=204), and elderly tumor-free smokers and non-smokers (ED, n=246). Results: CYP1A1*2 allele carriers demonstrated a clear-cut association with SCC: the adjusted odds ratios (OR) were 2.22 (95% CI=1.06–4.63) and 2.27 (95% CI=1.14–4.52) when HD and ED were used as referents, respectively. CYP1A1*2(+)/GSTM1(-) combined genotypes were overrepresented in the SCC patients (14/70, 20.0%) and underrepresented in the ED (19/246, 7.7%) as compared to the intermediate prevalence in the HD (26/204, 12.7%); the adjusted OR for SCC versus ED reached 3.85 (95% CI=1.43–10.33). Conclusions: In agreement with some literature data, our results support the concerted role of CYP1A1 and GSTM1 at-risk genotypes in SCC predisposition.
Similar content being viewed by others
Abbreviations
- LC:
-
Lung cancer
- SCC:
-
Squamous cell carcinoma
- HD:
-
Healthy donors
- ED:
-
Elderly donors
- OR:
-
Odds ratio
- CI:
-
Confidence interval
References
Belogubova EV, Togo AV, Karpova MB, Kuligina ESh, Buslova KG, Ulibina JM, Lemehov VG, Romanenko SM, Shutkin VA, Hanson KP, Hirvonen A, Imyanitov EN (2004) A novel approach for assessment of cancer predisposing roles of GSTM1 and GSTT1 genes: use of putatively cancer resistant elderly tumor-free smokers as the referents Lung Cancer 43:259–266
Bartsch H, Nair U, Risch A, Rojas M, Wikman H, Alexandrov K (2000) Genetic polymorphism of CYP genes, alone or in combination, as a risk modifier of tobacco-related cancers Cancer Epidemiol Biomarkers Prev 9:3–28
Fryer AA, Jones PW (1999) Interactions between detoxifying enzyme polymorphisms and susceptibility to cancer IARC Sci Publ 148:303–322
Garte S, Crosti F (1999) A nomenclature system for metabolic gene polymorphisms IARC Sci Publ 148:5–12
Hayashi S, Watanabe J, Nakachi K, Kawajiri K (1991) Genetic linkage of lung cancer-associated MspI polymorphisms with amino acid replacement in the heme binding region of the human cytochrome P450IA1 gene J Biochem (Tokyo) 110:407–411
Hayashi S, Watanabe J, Kawajiri K., (1992) High susceptibility to lung cancer analyzed in terms of combined genotypes of P450IA1 and Mu-class glutathione S-transferase genes Jpn J Cancer Res 83:866–870
Hecht SS (1997) Tobacco and cancer: approaches using carcinogen biomarkers and chemoprevention Ann NY Acad Sci 833:91–111
Hirvonen A (2004) Genetic susceptibility to PAH-induced carcinogenesis. In: Luch A (ed) The carcinogenic effects of polycyclic aromatic hydrocarbons. Imperial College Press, London, 353–377
Imyanitov EN, Togo AV, Hanson KP (2004) Searching for cancer-associated gene polymorphisms: promises and obstacles Cancer Lett 204:3–14
Imyanitov EN, Kuligina ESh, Belogubova EV, Togo AV, Hanson KP (2005) Mechanisms of lung cancer Drug Discov Today Dis Mech 2: 213–223
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 polymorphisms in a Japanese population Carcinogenesis 16:2331–2336
Kiyohara C, Otsu A, Shirakawa T, Fukuda S, Hopkin JM (2002) Genetic polymorphisms and lung cancer susceptibility: a review Lung Cancer 37:241–256
Le Marchand L, Sivaraman L, Pierce L, Seifried A, Lum A, Wilkens LR, Lau AF (1998) Associations of CYP1A1, GSTM1, and CYP2E1 polymorphisms with lung cancer suggest cell type specificities to tobacco carcinogens Cancer Res 58:4858–4863
Nakachi K, Imai K, Hayashi S, 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
Vineis P, Veglia F, Benhamou S, Butkiewicz D, Cascorbi I, Clapper ML, Dolzan V, Haugen A, Hirvonen A, Ingelman-Sundberg M, Kihara M, Kiyohara C, Kremers P, Le Marchand L, Ohshima S, Pastorelli R, Rannug A, Romkes M, Schoket B, Shields P, Strange RC, Stucker I, Sugimura H, Garte S, Gaspari L, Taioli E (2003) CYP1A1 T3801 C polymorphism and lung cancer: a pooled analysis of 2451 cases and 3358 controls. Int J Cancer 104:650–657
Vineis P, Veglia F, Anttila S, Benhamou S, Clapper ML, Dolzan V, Ryberg D, Hirvonen A, Kremers P, Le Marchand L, Pastorelli R, Rannug A, Romkes M, Schoket B, Strange RC, Garte S, Taioli E (2004) CYP1A1, GSTM1 and GSTT1 polymorphisms and lung cancer: a pooled analysis of gene-gene interactions Biomarkers 9:298–305
Acknowledgements
We are grateful to Prof. Vladimir G. Lemehov for providing clinical expertize. We also thank Mrs. Olga S. Yatsuk, Olga A. Zaitseva and Liudmila V. Rikunova for the technical assistance. The work was supported by INTAS (grant 99–01391) and RFBR (grant 02–04–49794)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Belogubova, E.V., Ulibina, Y.M., Suvorova, I.K. et al. Combined CYP1A1/GSTM1 at-risk genotypes are overrepresented in squamous cell lung carcinoma patients but underrepresented in elderly tumor-free subjects. J Cancer Res Clin Oncol 132, 327–331 (2006). https://doi.org/10.1007/s00432-005-0071-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-005-0071-7