DOI QR코드

DOI QR Code

Genetic Variants of CYP2D6 Gene and Cancer Risk: A HuGE Systematic Review and Meta-analysis

  • Zhou, Li-Ping (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) ;
  • Luan, Hong (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) ;
  • Dong, Xi-Hua (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) ;
  • Jin, Guo-Jiang (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) ;
  • Man, Dong-Liang (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University) ;
  • Shang, Hong (Department of Laboratory Medicine, the First Affiliated Hospital of China Medical University)
  • Published : 2012.07.31

Abstract

Objective: Genetic polymorphisms in metabolic enzymes are associated with numerous cancers. A large number of single nucleotide polymorphisms (SNPs) in the CYP2D6 gene have been reported to associate with cancer susceptibility. However, the results are controversial. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to summarize the evidence for associations. Methods: Studies focusing on the relationship between CYP2D6 gene polymorphisms and susceptibility to cancer were selected from the Pubmed, Cochrane library, Embase, Web of Science, Springerlink, CNKI and CBM databases. Data were extracted by two independent reviewers and the meta-analysis was performed with Review Manager Version 5.1.6 and STATA Version 12.0 software. Odds ratios (ORs) with 95% confidence intervals (95%CIs) were calculated. Results: According to the inclusion criteria, forty-three studies with a total of 7,009 cancer cases and 9,646 healthy controls, were included in the meta-analysis. The results showed that there was a positive association between heterozygote (GC) of rs1135840 and cancer risk (OR=1.92, 95%CI: 1.14-3.21, P=0.01). In addition, we found that homozygote (CC) of rs1135840 might be a protective factor for cancer (OR=0.58, 95%CI: 0.34-0.97, P=0.04). Similarly, the G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 had negative associations with cancer risk (OR=0.69, 95%CI: 0.48-0.99, P=0.04; OR=0.60, 95%CI: 0.38-0.94, P=0.03; OR=0.50, 95%CI: 0.26-0.95, P=0.03; respectively). Conclusion: This meta-analysis suggests that CYP2D6 gene polymorphisms are involved in the pathogenesis of various cancers. The heterozygote (GC) of rs1135840 in CYP2D6 gene might increase the risk while the homozygote (CC) of rs1135840, G allele and G carrier (AG + GG) of rs16947 and heterozygote (A/del) of rs35742686 might be protective factors.

Keywords

References

  1. Abraham JE, Maranian MJ, Driver KE, et al (2011). CYP2D6 gene variants and their association with breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev, 20, 1255-8. https://doi.org/10.1158/1055-9965.EPI-11-0321
  2. Agundez JA (2004). Cytochrome P450 gene polymorphism and cancer. Curr Drug Metab, 5, 211-24. https://doi.org/10.2174/1389200043335621
  3. Agundez JA, Jimenez-Jimenez FJ, Luengo A, et al (1995). Association between the oxidation polymorphism and early onset of Paekinson's disease. Clin Pharmacol Ther, 57, 291-8. https://doi.org/10.1016/0009-9236(95)90154-X
  4. Agundez JA, Ledesma MC, Benitez J, et al (1995). CYP2D6 genes and risk of liver cancer. Lancet, 345, 830-1. https://doi.org/10.1016/S0140-6736(95)92965-7
  5. Agundez JA, Martinez C, Ladero JM, et al (1994). Debrisoquin oxidation genotype and susceptibility to lung cancer. Clin Pharmacol Ther, 55, 10-4. https://doi.org/10.1038/clpt.1994.3
  6. Agundez JA, Martinez C, Olivera M, et al (1998). Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk. Br J Cancer, 78, 1361-7. https://doi.org/10.1038/bjc.1998.685
  7. Agundez JA, Olivera M, Ladero JM, et al (1996). Increased risk for hepatacellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics, 6, 501-12. https://doi.org/10.1097/00008571-199612000-00003
  8. Altayli E, Gunes S, Yilmaz AF, et al (2009). CYP1A2, CYP2D6, GSTM1, GSTP1, and GSTT1 gene polymorphisms in patients with bladder cancer in a Turkish population. Int Urol Nephrol, 41, 259-66. https://doi.org/10.1007/s11255-008-9444-6
  9. Aydin-Sayitoglu M, Hatirnaz O, Erensoy N, et al (2006). Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias. Am J Hematol, 81, 162-70. https://doi.org/10.1002/ajh.20434
  10. Bonanni B, Macis D, Maisonneuve P, et al (2006). Polymorphism in the CYP2D6 tamoxifen-metabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial. J Clin Oncol, 24, 3708-9. https://doi.org/10.1200/JCO.2006.06.8072
  11. Butler WJ, Ryan P, Roberts-Thomson IC (2001). Metabolic genotypes and risk for colorectal cancer. J Gastroenterol Hepatol, 16, 631-5. https://doi.org/10.1046/j.1440-1746.2001.02501.x
  12. Chen HC, Hu WX, Liu QX, et al (2008). Genetic polymorphisms of metabolic enzymes CYP1A1, CYP2D6, GSTM1 and GSTT1 and leukemia susceptibility. Eur J Cancer Prev, 17, 251-8. https://doi.org/10.1097/CEJ.0b013e3282b72093
  13. Chen SQ, Xu L, Ma GJ, Xue KX (2004). Genetic polymorphism of CYP2D6 and its relation to lung cancer susceptibility. Tumor Mar, 24, 96-98.
  14. Febbo PG, Kantoff PW, Giovannucci E, et al (1998). Debrisoquine hydroxylase (CYP2D6) and prostate cancer. Cancer Epidemiol Biomarkers Prev, 7, 1075-8.
  15. Foster BC, Vandenhoek S, Hana J, et al (2003). In vitro inhibition of human cytochrome P450-mediated metabolism of marker substrates by natural products. Phytomedicine, 10, 334-42. https://doi.org/10.1078/094471103322004839
  16. Fukatsu T, Hirokawa Y, Araki T, et al (2004). Genetic polymorphisms of hormone-related genes and prostate cancer risk in the Japanese population. Anticancer Res, 24, 2431-7.
  17. Gajecka M, Rydzanicz M, Jaskula-Sztul R, et al (2005). CYP1A1, CYP2D6, CYP2E1, NAT2, GSTM1 and GSTT1 polymorphisms or their combinations are associated with the increased risk of the laryngeal squamous cell carcinoma. Mutat Res, 574, 112-23. https://doi.org/10.1016/j.mrfmmm.2005.01.027
  18. Garcia-Barcelo M, Chow LY, Chiu HF, et al (2000). Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population. Clin Chem, 46, 18-23.
  19. Gomes L, Lemos MC, Paiva I, et al (2005). CYP2D6 genetic polymorphisms are associated with susceptibility to pituitary tumors. Acta Med Port, 18, 339-43.
  20. Gonzalez MV, Alvarez V, Pello MF, et al (1998). Genetic polymorphism of N-acetyltransferase-2, glutathione S-transferase-M1, and cytochromes P450IIE1 and P450IID6 in the susceptibility to head and neck cancer. J Clin Pathol, 51, 294-8. https://doi.org/10.1136/jcp.51.4.294
  21. Guo Z, Zhou Q, Zhu W, et al (2005). A case-control study on the association between genetic polymorphisms of metabolizing enzymes CYP2D6 and susceptibility to lung cancer. Zhongguo Fei Ai Za Zhi, 8, 89-94.
  22. Gutman G, Morad T, Peleg B, et al (2009). CYP1A1 and CYP2D6 gene polymorphisms in Israeli Jewish women with cervical cancer. Int J Gynecol Cancer, 19, 1300-2. https://doi.org/10.1111/IGC.0b013e3181b9fa5d
  23. Higgins JP and Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58. https://doi.org/10.1002/sim.1186
  24. Hu YL, Gao Y, Zhang Q (1998). Genetic polymorphisms of CYP1A1, 2D6 and GSTM1 related with susceptibility to lung cancer. Tumor, 18, 269-71.
  25. Ji L, Pan S, Marti-Jaun J, et al (2002). Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel $^\ast14B$ allele in mainland Chinese. Clin Chem, 48, 983-88.
  26. Jin Y, Desta Z, Stearns V, et al (2005). CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst, 97, 30-9. https://doi.org/10.1093/jnci/dji005
  27. Khedhaier A, Hassen E, Bouaouina N, et al (2008). Implication of Xenobiotic Metabolizing Enzyme gene (CYP2E1, CYP2C19, CYP2D6, mEH and NAT2) polymorphisms in breast carcinoma. BMC Cancer, 8, 109. https://doi.org/10.1186/1471-2407-8-109
  28. Kimura S, Umeno M, Skoda RC, et al (1989). The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet, 45, 889-904.
  29. Krajinovic M, Labuda D, Richer C, et al (1999). Susceptibility to childhood acute lymphoblastic leukemia: influence of CYP1A1, CYP2D6, GSTM1, and GSTT1 genetic polymorphisms. Blood, 93, 1496-501.
  30. Kroemer HK, Eichelbaum M (1995). "It's the genes, stupid". Molecular bases and clinical consequences of genetic cytochrome P450 2D6 polymorphism. Life Sciences, 56, 2285-98. https://doi.org/10.1016/0024-3205(95)00223-S
  31. Ladona MG, Abildua RE, Ladero JM, et al (1996). CYP2D6 genotypes in Spanish women with breast cancer. Cancer Lett, 99, 23-8. https://doi.org/10.1016/0304-3835(95)04033-1
  32. Legrand M, Stucker I, Marez D, et al (1996). Influence of a mutation reducing the catalytic activity of the cytochrome P450 CYP2D6 on lung cancer susceptibility. Carcinogenesis, 17, 2267-9. https://doi.org/10.1093/carcin/17.10.2267
  33. Lemos MC, Carrilho F, Rodrigues F, et al (2007). Genetic polymorphism of CYP2D6 influences susceptibility to papillary thyroid cancer. Clin Endocrinol (Oxf), 67, 180-3. https://doi.org/10.1111/j.1365-2265.2007.02858.x
  34. Lemos MC, Cabrita FJ, Silva HA, et al (1999). Genetic polymorphism of CYP2D6, GSTM1 and NAT2 and susceptibility to haematological neoplasias. Carcinogenesis, 20, 1225-9. https://doi.org/10.1093/carcin/20.7.1225
  35. Lewis DF (2004). Varieties: the human cytochromes P450. Pharmacogenomics, 5, 305-18. https://doi.org/10.1517/phgs.5.3.305.29827
  36. Li H, Feng L, Xu Y, et al (2006). The association of CYP2D6 $^\ast10$ polymorphism with breast cancer risk and clinico-pathologic characteristics in Chinese women. Acta Oncol, 45, 597-601. https://doi.org/10.1080/02841860600660803
  37. Li WY, Lai BT, Zhan XP (2004). The relationship between genetic polymorphism of mebabolizing enzymes and the genetic susceptibility to lung cancer. Chin J Epidemiol, 25, 1042-45.
  38. Liang GY (2005). Studies on susceptibility genes of lung cancer in Chinese Han population and rapid detection techniques of single nucleotides polymorphisms. Southeast University, 1-108.
  39. Lim JS, Chen XA, Singh O, et al (2011). Impact of CYP2D6, CYP3A5, CYP2C9 and CYP2C19 polymorphisms on tamoxifen pharmacokinetics in Asian breast cancer patients. Br J Clin Pharmacol, 71, 737-50. https://doi.org/10.1111/j.1365-2125.2011.03905.x
  40. Liu CZ, Jiang F, Bian JC, et al (2002). Cytochrome P450 2D6 gene polymorphism and susceptibility to hepatocellular carcinoma research. Chinese Journal of Cancer, 21, 1016-17.
  41. London SJ, Daly AK, Leathart JB, et al (1997). Genetic polymorphism of CYP2D6 and lung cancer risk in African-Americans and Caucasians in Los Angeles County. Carcinogenesis, 18, 1203-14. https://doi.org/10.1093/carcin/18.6.1203
  42. Luo YP, Chen HC, Khan MA, et al (2011). Genetic polymorphisms of metabolic enzymes-CYP1A1, CYP2D6, GSTM1, and GSTT1, and gastric carcinoma susceptibility. Tumour Biol, 32, 215-22. https://doi.org/10.1007/s13277-010-0115-8
  43. Majumdar S, Mondal BC, Ghosh M, et al (2008). Association of cytochrome P450, glutathione S-transferase and N-acetyl transferase 2 gene polymorphisms with incidence of acute myeloid leukemia. Eur J Cancer Prev, 17, 125-32. https://doi.org/10.1097/CEJ.0b013e3282b6fd68
  44. Meyer UA, Zanger UM (1997). Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol, 37, 269-96. https://doi.org/10.1146/annurev.pharmtox.37.1.269
  45. Mochizuki J, Murakami S, Sanjo A, et al (2005). Genetic polymorphisms of cytochrome P450 in patients with hepatitis C virus-associated hepatocellular carcinoma. J Gastroenterol Hepatol, 20, 1191-7. https://doi.org/10.1111/j.1440-1746.2005.03808.x
  46. Morrow PK, Serna R, Broglio K, et al (2012). Effect of CYP2D6 polymorphisms on breast cancer recurrence. Cancer, 118, 1221-7. https://doi.org/10.1002/cncr.26407
  47. Ouerhani S, Marrakchi R, Bouhaha R, et al (2008). The role of $CYP2D6^\ast4$ variant in bladder cancer susceptibility in Tunisian patients. Bull Cancer, 95, E1-4.
  48. Peters JL, Sutton AJ, Jones DR, et al (2006). Comparison of two methods to detect publication bias in meta-analysis. JAMA, 295, 676-80. https://doi.org/10.1001/jama.295.6.676
  49. Roberts RL, Kennedy MA (2006). Rapiddetection of common cytochrome P450 2D6 alleles in Caucasians. Clin Chmi Acta, 366, 348-51. https://doi.org/10.1016/j.cca.2005.11.008
  50. Shaw GL, Falk RT, Frame JN, et al (1998). Genetic polymorphism of CYP2D6 and lung cancer risk. Cancer Epidemiol Biomarkers Prev, 7, 215-9.
  51. Singh D, Kashyap A, Pandey RV, Saini KS (2011). Novel advances in cytochrome P450 research. Drug Discov Today, 16, 793-9. https://doi.org/10.1016/j.drudis.2011.08.003
  52. Singh MS, Francis PA, Michael M. (2011). Tamoxifen, cytochrome P450 genes and breast cancer clinical outcomes. Breast, 20, 111-8. https://doi.org/10.1016/j.breast.2010.11.003
  53. Sistonen J, Sajantila A, Lao O, et al (2007). CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics, 17, 93-101.
  54. Sobti RC, Al-Badran AI, Sharma S, et al (2005). Genetic polymorphisms of CYP2D6, GSTM1, and GSTT1 genes and bladder cancer risk in North India. Cancer Genet Cytogenet, 156, 68-73. https://doi.org/10.1016/j.cancergencyto.2004.04.001
  55. Sobti RC, Sharma S, Joshi A, et al (2003). CYP1A1 and CYP2D6 polymorphism and risk of lung cancer in a North Indian population. Biomarkers, 8, 415-28. https://doi.org/10.1080/13547500310001619860
  56. Surekha D, Sailaja K, Rao DN, et al (2010). Association of a CYP17 gene polymorphism with development of breast cancer in India. Asian Pac J Cancer Prev, 11, 1653-7.
  57. Surekha D, Sailaja K, Rao DN, et al (2010). $CYP2D6^\ast4$ polymorphisms and breast cancer risk. Biology and Medicine, 2, 49-55.
  58. Topic E, Stefanovic M, Ivanisevic AM, et al (2000). The cytochrome P450 2D6 (CYP2D6) gene polymorphism among breast and head and neck cancer patients. Clin Chim Acta, 296, 101-9. https://doi.org/10.1016/S0009-8981(00)00221-7
  59. Torresan C, Oliveira MM, Torrezan GT, et al (2008). Genetic polymorphisms in oestrogen metabolic pathway and breast cancer: a positive association with combined CYP/GST genotypes. Clin Exp Med, 8, 65-71. https://doi.org/10.1007/s10238-008-0159-x
  60. von Elm E, Altman DG, Egger M, et al (2007). STROBE Initiative: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Epidemiology, 18, 800-804. https://doi.org/10.1097/EDE.0b013e3181577654
  61. Wexler D, Courtney R, Richards W, et al (2004). Effect of posaconazole on cytochrome P450 enzymes: a randomized, open-label, two-way crossover study. Eur J Pharm Sci, 21, 645-53. https://doi.org/10.1016/j.ejps.2004.01.005
  62. Wilkinson GR (2005). Drug metabolism and variability among patients in drug response. N Engl J Med, 352, 2211-21. https://doi.org/10.1056/NEJMra032424
  63. Wundrack I, Meese E, Mullenbach R, Blin N (1994). Debrisoquine hydroxylase gene polymorphism in meningioma. Acta Neuropathol, 88, 472-74. https://doi.org/10.1007/BF00389501
  64. Yan Z, Wu YM, Wu YJ (2008). $CYP2D6^\ast10$ polymorphisms and lung cancer susceptibility. Zhongguo Yi Xue Ke Xue Yuan Xue Bao, 30, 564-8.
  65. Zhang L, Liu JL, Zhang YJ, Wang H (2011). Association between $HLA-B^\ast27$ polymorphisms and ankylosing spondylitis in Han populations: a meta-analysis. Clin Exp Rheumatol, 29, 285-92.
  66. Zhou SF (2009). Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet, 48, 689-723. https://doi.org/10.2165/11318030-000000000-00000
  67. Zhou JL, Yao ZJ, Zeng ZP, Zhao XR (2011). Case-control study for the relationship of CYP1A1 and CYP2D6 polymorphisms with the genetic susceptibility to lung cancer. J Guangdong Phar, 27, 528-31.
  68. Zintzaras E, Ioannidis JP (2005). Heterogeneity testing in meta-analysis of genome searches. Genet Epidemiol, 28, 123-37. https://doi.org/10.1002/gepi.20048

Cited by

  1. GSTP1 Gene Ile105Val Polymorphism Causes an Elevated Risk for Bladder Carcinogenesis in Smokers vol.14, pp.11, 2013, https://doi.org/10.7314/APJCP.2013.14.11.6375
  2. Clinical, Cytogenetic and CYP1A1 exon-1 Gene Mutation Analysis of Beedi Workers in Vellore Region, Tamil Nadu vol.14, pp.12, 2013, https://doi.org/10.7314/APJCP.2013.14.12.7555
  3. Leu), GSTM1 (null), and GSTT1 (null) Polymorphisms and Bladder Cancer Risk in a Turkish Population vol.14, pp.6, 2013, https://doi.org/10.7314/APJCP.2013.14.6.3925
  4. CYP2D6 T188C variant is associated with lung cancer risk in the Chinese population vol.34, pp.4, 2013, https://doi.org/10.1007/s13277-013-0755-6
  5. CYP2D6 Genotype and Risk of Recurrence in Tamoxifen Treated Breast Cancer Patients vol.16, pp.15, 2015, https://doi.org/10.7314/APJCP.2015.16.15.6783
  6. Lessons Learned From Past Gene-Environment Interaction Successes vol.186, pp.7, 2017, https://doi.org/10.1093/aje/kwx230