Gene variants of CYP1A1 and CYP2D6 and the risk of childhood acute lymphoblastic leukaemia; outcome of a case control study from Kashmir, India

Document Type: Original article

Authors

1 Department of Biochemistry, University of Kashmir, Hazratbal Srinagar, Jammu and Kashmir, India

2 Department of Clinical Heamatology, Sher-e-Kashmir Institute of Medical Sciences (SKIMS), Srinagar, Jammu and Kashmir, India

3 Center of Research Development (CORD), University of Kashmir Srinagar, Jammu and Kashmir, India

Abstract

Studies on associations of various polymorphisms in xenobiotic metabolizing genes with different cancers including acute lymphoblastic leukaemia (ALL) are mixed and inconclusive. The current study analyzed the relationship between polymorphisms of phase I xenobiotic metabolizing enzymes, cytochromes P450 1A1 (CYP1A1) and CYP2D6 and childhood ALL in Kashmir, India. We recruited 200 confirmed ALL cases, and an equal number of controls, matched for sex, age and district of residence to the respective case. Information was obtained on various lifestyle and environmental factors in face to face interviews with the parents/attendants of each subject. Genotypes of CYP1A1 and CYP2D6 were analyzed by polymerase chain reaction and restriction fragment length polymorphism method. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs). Compared to the GG genotype, we found a higher ALL risk in subjects who harbored variant (AA) genotype (OR=20.9; 95% CI: 6.01-73.1, P<0.0001) and AG genotype (OR=42.6; 95% CI: 8.3-217.5, P<0.0001) of CYP2D6*4 polymorphism. Although, we found a significant association of CYP1A1*2A polymorphism with ALL risk, but the risk did not persist in the adjusted model (OR=6.76; 95% CI: 0.63–71.8, P=0.100). The study indicates that unlike CYP1A1*2A, CYP2D6*4 polymorphism is associated with ALL risk. However, more replicative studies with larger sample size are needed to substantiate our findings.

Keywords


1. Infante-Rivard C, Labuda D, Krajinovic M, Sinnett D. Risk of childhood leukemia associated with exposure to pesticides and with gene polymorphisms. Epidemiology 1999;10:481-487.

2. Perera FP. Molecular epidemiology: Insights into cancer susceptibility, risk assessment, and prevention. J Natl Cancer Inst 1996;88:496.

3. Brisson GD, Alves LR, Pombo-de-Oliveira MS. Genetic susceptibility in childhood acute leukaemias: a systematic review. Ecancermedicalscience 2015;9:539.

4. Krajinovic M, Labuda D, Mathonnet G, Labuda M, Moghrabi A, Champagne J, Sinnett D. Polymorphisms in genes encoding drugs and xenobiotic metabolizing enzymes, DNA repair enzymes, and response to treatment of childhood acute lymphoblastic leukemia. Clin Cancer Res 2002;8:802-810.

5. Gra OA, Kozhekbaeva ZM, Makarova OV, Samochatova EV, Nasedkina TV. Polymorphism of biotransformation genes and risk of relapse in childhood acute leukemia. Balkan J Med Genet 2009;12:21-35.

6. Rieder CRM, Ramsden DB, Williams AC. Cytochrome P450 1B1mRNA in the human central nervous system. Mol Pathol 1998;51:138-142.

7. Krajinovic M, Labuda D, Sinnett D. Childhood acute lymphoblastic leukemia: genetic determinants of susceptibility and disease outcome. Rev Environ Health 2001;16:263-279.

8. Nazki FH, Masood A, Banday MA, Bhat A, Ganai BA. Thymidylate synthase enhancer region polymorphism not related to susceptibility to acute lymphoblastic leukemia in the Kashmir population. Genet Mol Res 2012;11: 906-917.

9. Muzaffar J, Shabir A, Ishrat R, Sheikh Q, Tariq R. Pattern and clinical profile of childhood malignancies in Kashmir India. JK- Practitioner 2015;20:12-16.

10. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR, Sultan C. Proposed revised criteria for the classification of acute myeloid leukemia. A report of the French- American-British Cooperative group. Br J Haematol 1976;33: 451-458.

11.Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009; 114:937-951.

12. Sambrook J, Rusell DW. Molecular Cloning: A Laboratory Manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory, 2001.

13. Cascorbi I, Brockmöller J, Roots I. A C4887A polymorphism in exon 7 of human CYP1A1: population frequency, mutation linkages, and impact on lung cancer susceptibility. Cancer Res 1996;56: 4965-4969.

14. Krajinovic M, Labuda D, Richer C, Karimi S, Sinnett D. Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood 1999; 93:1496-501.

15. Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene 2006;25:1679-1679.

16. Zeng W, Li Y, Lu E, Ma M. CYP1A1 rs1048943 and rs4646903 polymorphisms associated with laryngeal cancer susceptibility among Asian populations: a meta‐analysis. J Cell Mol Med 2016;20:287-293.

17. Duarte EC, Ribeiro DC, Gomez MV, Ramos-Jorge ML, Gomez RS. Genetic polymorphisms of carcinogen metabolizing enzymes are associated with oral leukoplakia development and p53 overexpression. Anticancer Res 2008;28:1101- 1106.

18. Jang JH, Cotterchio M, Borgida A, Gallinger S, Cleary SP. Genetic variants in carcinogen-metabolizing enzymes, cigarette smoking and pancreatic cancer risk. Carcinogenesis 2012;33:818- 827.

19. Catsburg C, Joshi AD, Corral R, Lewinger JP, Koo J, John EM, Ingles SA, Stern MC. Polymorphisms in carcinogen metabolism enzymes, fish intake, and risk of prostate cancer. Carcinogenesis 2012;33:1352-1359.

20. Justenhoven C. Polymorphisms of phase I and phase II enzymes and breast cancer risk. Front Genet 2012;3:258.

21. Bolufer P, Barragan E, Collado M, Cervera J, Lopez JA, Sanz MA. Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leuk Res 2006;30:1471-91.

22. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, Wolf CR. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 1990;347:773-776.

23. Lemos MC, Cabrita FJ, Silva HA. Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis 1999;20: 1225-1229.

24. Silveira, VS, Canalle R, Scrideli CA, Queiroz RGP, Tone LG. Role of the CYP2D6, EPHX1, MPO, and NQO1 genes in the susceptibility to acute lymphoblastic leukemia in Brazilian children. Environ Mol Mutagen 2010;51:48–56.

25. Joseph T, Kusumakumary P, Chacko P, Abraham A, Radhakrishna Pillai M. Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children. Pediatr Blood Cancer 2004; 43:560-567.

26. Sim SC, Ingelman-Sundberg M. The human cytochrome P450 Allele Nomenclature Committee Web site: submission criteria, procedures, and objectives. Methods Mol Biol 2006; 320:183-191.

27. Whyatt RM, Perera FP. Application of biologic markers to studies of environmental risks in children and the developing fetus. Environ Health Perspect 1995;103(Suppl. 6):105-110.

28. Lu J, Zhao Q, Zhai YJ, He HR, Yang LH, Gao F, Zhou RS, Zheng J, Ma XC. Genetic polymorphisms of CYP1A1 and risk of leukemia: a meta-analysis. Onco Targets Ther 2015;8:2883-2902.

29. Roman E, Lightfoot T, Smith AG, Forman MR, Linet MS, Robison L, Simpson J, Kaatsch P, Grell K, Frederiksen K, Schüz J. Childhood acute lymphoblastic leukaemia and birth weight: insights from a pooled analysis of case-control data from Germany, the United Kingdom and the United States . Eur J Cancer 2013;49:1437- 1447.

30. Stejskalova L, Pavek P. The function of cytochrome P450 1A1 enzyme (CYP1A1) and aryl hydrocarbon receptor (AhR) in the placenta. Curr Pharm Biotechnol 2011; 12:715-730.

31. Juchau MR. Drug biotransformation in the placenta. Pharmacol Ther 1980;8:501-524.

32. Liu R, Zhang L, McHale CM, Hammond SK. Paternal smoking and risk of childhood acute lymphoblastic leukemia: systematic review and met-analysis. J Oncol 2011;2011:854584.

33. Milne E, Greenop KR, Scott RJ,  Bailey HD, Attia J, Dalla-Pozza L, de Klerk NH, Armstrong BK. Parental prenatal smoking and risk of childhood acute lymphoblastic leukemia. Am J Epidemiol 2012;175:43-53.

34. Slatter TL, Park L, Anderson K,  Lailai-Tasmania V, Herbison P, Clow W, Royds JA, Devenish C, Hung NA. Smoking during pregnancy causes double-strand DNA break damage to the placenta. Hum Pathol 2014;45:17-26.

35. Linet MS, Kim KP, Rajaraman P. Children’s exposureto diagnostic medical radiation and cancer risk:epidemiologic and dosimetric considerations. Pediatric Radiol 2009;39 (suppl 1):S4-26.

36. Wiemels J. Perspectives on the causes of childhood leukemia. Chem Biol Interact 2012;196:59-67.

37. Jin MW, Xu SM, An Q, Wang P. A review of risk factors for childhood leukemia. Eur Rev Med Pharmacol Sci 2016;20:3760-3764.

38. Bartley K, Metayer C, Selvin S, Ducore J, Buffler P. Diagnostic X-rays and risk of childhood leukaemia. Int J Epidemiol 2010;39:1628-1637.