Tumor Biology

, Volume 34, Issue 2, pp 649–660 | Cite as

CYP3A4*1B polymorphism and cancer risk: A HuGE review and meta-analysis

  • Li-Ping Zhou
  • Fan YaoEmail author
  • Hong Luan
  • Yin-Ling Wang
  • Xi-Hua Dong
  • Wen-Wen Zhou
  • Qi-Hui Wang
Research Article


CYP450 3A4 (CYP3A4), encoded by the CYP3A4 gene, is a major enzyme catalyzing the metabolism of both endogenous and exogenous agents that may play a role in the etiology of carcinogenesis. Several potentially functional polymorphisms of the CYP3A4 gene have been implicated in cancer risk, but individually published studies have shown inconclusive results. The aim of this Human Genome Epidemiology (HuGE) review and meta-analysis was to investigate the association between CYP3A4*1B (rs2740574 A > G) polymorphism and cancer risk. Eleven studies were included with a total of 3,810 cancer patients and 3,173 healthy controls. We found that the G allele and GG genotype of CYP3A4*1B polymorphism were associated with increased risk of cancers using the fixed effects model (allele model: odds ratio (OR) = 1.24, 95 %CI: 1.09–1.42, P = 0.001; recessive model: OR = 1.77, 95 %CI: 1.30–2.41, P < 0.001; homozygous model: OR = 1.72, 95 %CI: 1.19–2.47, P = 0.004). Subgroup analyses by cancer type showed that the G allele and G carrier (AG + GG) of CYP3A4*1B polymorphism had significant associations with increased risk of prostate cancer, but not with breast cancer, leukemia, or other cancers. With further subgroup analysis based on different ethnicities, the results indicated that the GG genotype of CYP3A4*1B polymorphism might increase the risk of cancer among African populations. However, similar associations were not observed among Caucasian and Asian populations. Results from the current meta-analysis indicate that the G allele and GG genotype of CYP3A4*1B polymorphism might be associated with increased cancer risk, especially for prostate cancer among African populations.


CYP3A4 Polymorphism Cancer risk Meta-analysis 



This study was supported by a grant from the Science and Technology Research Project of the Higher Education Department of Liaoning Province (No. L2010695).

Conflicts of interest



  1. 1.
    Patton GC, Coffey C, Sawyer SM, Viner RM, Haller DM, Bose K, Vos T, Ferguson J, Mathers CD. Global patterns of mortality in young people: a systematic analysis of population health data. Lancet. 2009;374:881–92.PubMedCrossRefGoogle Scholar
  2. 2.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA: a cancer journal for clinicians. 2011;61:69–90.CrossRefGoogle Scholar
  3. 3.
    Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: Globocan 2008. International journal of cancer Journal international du cancer. 2010;127:2893–917.PubMedCrossRefGoogle Scholar
  4. 4.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a cancer journal for clinicians. 2012;62:10–29.CrossRefGoogle Scholar
  5. 5.
    Esteller M. Epigenetics in cancer. N Engl J Med. 2008;358:1148–59.PubMedCrossRefGoogle Scholar
  6. 6.
    Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27–36.PubMedCrossRefGoogle Scholar
  7. 7.
    Loktionov A. Common gene polymorphisms, cancer progression and prognosis. Cancer Lett. 2004;208:1–33.PubMedCrossRefGoogle Scholar
  8. 8.
    Yang X, Zhang B, Molony C, Chudin E, Hao K, Zhu J, Gaedigk A, Suver C, Zhong H, Leeder JS, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich RG, Slatter JG, Schadt EE, Kasarskis A, Lum PY. Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver. Genome Res. 2010;20:1020–36.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang J. Cyp3a polymorphisms and immunosuppressive drugs in solid-organ transplantation. Expert Rev Mol Diagn. 2009;9:383–90.PubMedCrossRefGoogle Scholar
  10. 10.
    Dally H, Edler L, Jager B, Schmezer P, Spiegelhalder B, Dienemann H, Drings P, Schulz V, Kayser K, Bartsch H, Risch A. The cyp3a4*1b allele increases risk for small cell lung cancer: effect of gender and smoking dose. Pharmacogenetics. 2003;13:607–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Sarma AV, Dunn RL, Lange LA, Ray A, Wang Y, Lange EM, Cooney KA. Genetic polymorphisms in cyp17, cyp3a4, cyp19a1, srd5a2, igf-1, and igfbp-3 and prostate cancer risk in African-American men: the flint men's health study. Prostate. 2008;68:296–305.PubMedCrossRefGoogle Scholar
  12. 12.
    Bozina N, Bradamante V, Lovric M. Genetic polymorphism of metabolic enzymes p450 (cyp) as a susceptibility factor for drug response, toxicity, and cancer risk. Arhiv za higijenu rada i toksikologiju. 2009;60:217–42.PubMedCrossRefGoogle Scholar
  13. 13.
    Nogal A, Coelho A, Catarino R, Morais A, Lobo F, Medeiros R. The cyp3a4 *1b polymorphism and prostate cancer susceptibility in a portuguese population. Cancer genetics and cytogenetics. 2007;177:149–52.PubMedCrossRefGoogle Scholar
  14. 14.
    Voso MT, Fabiani E, D'Alo F, Guidi F, Di Ruscio A, Sica S, Pagano L, Greco M, Hohaus S, Leone G. Increased risk of acute myeloid leukaemia due to polymorphisms in detoxification and DNA repair enzymes. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2007;18:1523–8.CrossRefGoogle Scholar
  15. 15.
    Ociepa-Zawal M, Rubis B, Filas V, Breborowicz J, Trzeciak WH. Studies on cyp1a1, cyp1b1 and cyp3a4 gene polymorphisms in breast cancer patients. Ginekologia polska. 2009;80:819–23.PubMedGoogle Scholar
  16. 16.
    da Costa BR, Cevallos M, Altman DG, Rutjes AW, Egger M. Uses and misuses of the strobe statement: Bibliographic study. BMJ open. 2011;1:e000048.PubMedCrossRefGoogle Scholar
  17. 17.
    Zhang L, Liu JL, Zhang YJ, Wang H. Association between hla-b*27 polymorphisms and ankylosing spondylitis in han populations: a meta-analysis. Clin Exp Rheumatol. 2011;29:285–92.PubMedGoogle Scholar
  18. 18.
    Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21:1539–58.PubMedCrossRefGoogle Scholar
  19. 19.
    Zintzaras E, Ioannidis JP. Heterogeneity testing in meta-analysis of genome searches. Genetic epidemiology. 2005;28:123–37.PubMedCrossRefGoogle Scholar
  20. 20.
    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA: the journal of the American Medical Association. 2006;295:676–80.CrossRefGoogle Scholar
  21. 21.
    Spurdle AB, Goodwin B, Hodgson E, Hopper JL, Chen X, Purdie DM, McCredie MR, Giles GG, Chenevix-Trench G, Liddle C. The cyp3a4*1b polymorphism has no functional significance and is not associated with risk of breast or ovarian cancer. Pharmacogenetics. 2002;12:355–66.PubMedCrossRefGoogle Scholar
  22. 22.
    Yuan XJ, Gu LJ, Zhao HJ, Tang JY, Xue HL, Chen J, Pan C, Chen J, Wang YP. Analysis of cytochrome p450 genotype polymorphism in chinese children with acute leukemia. J Appl Clin Pediatr. 2005;20:654–6.Google Scholar
  23. 23.
    Bangsi D, Zhou J, Sun Y, Patel NP, Darga LL, Heilbrun LK, Powell IJ, Severson RK, Everson RB. Impact of a genetic variant in cyp3a4 on risk and clinical presentation of prostate cancer among white and African-American men. Urol Oncol. 2006;24:21–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Bolufer P, Collado M, Barragan E, Cervera J, Calasanz MJ, Colomer D, Roman-Gomez J, Sanz MA. The potential effect of gender in combination with common genetic polymorphisms of drug-metabolizing enzymes on the risk of developing acute leukemia. Haematologica. 2007;92:308–14.PubMedCrossRefGoogle Scholar
  25. 25.
    Gervasini G, Garcia-Martin E, Ladero JM, Pizarro R, Sastre J, Martinez C, Garcia M, Diaz-Rubio M, Agundez JA. Genetic variability in cyp3a4 and cyp3a5 in primary liver, gastric and colorectal cancer patients. BMC cancer. 2007;7:118.PubMedCrossRefGoogle Scholar
  26. 26.
    Kato I, Cichon M, Yee CL, Land S, Korczak JF. African American-preponderant single nucleotide polymorphisms (snps) and risk of breast cancer. Cancer epidemiology. 2009;33:24–30.PubMedCrossRefGoogle Scholar
  27. 27.
    McDaniel DO, Thurber T, Lewis-Traylor A, Berry C, Barber WH, Zhou X, Bigler S, Vance R. Differential association of cytochrome p450 3a4 genotypes with onsets of breast tumors in African American versus caucasian patients. Journal of investigative medicine: the official publication of the American Federation for Clinical Research. 2011;59:1096–103.Google Scholar
  28. 28.
    Inoue K, Inazawa J, Nakagawa H, Shimada T, Yamazaki H, Guengerich FP, Abe T. Assignment of the human cytochrome p-450 nifedipine oxidase gene (cyp3a4) to chromosome 7 at band q22.1 by fluorescence in situ hybridization. The Japanese journal of human genetics. 1992;37:133–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Lamba JK, Lin YS, Schuetz EG, Thummel KE. Genetic contribution to variable human cyp3a-mediated metabolism. Advanced drug delivery reviews. 2002;54:1271–94.PubMedCrossRefGoogle Scholar
  30. 30.
    Lee SJ, Goldstein JA. Functionally defective or altered cyp3a4 and cyp3a5 single nucleotide polymorphisms and their detection with genotyping tests. Pharmacogenomics. 2005;6:357–71.PubMedCrossRefGoogle Scholar
  31. 31.
    Keshava C, McCanlies EC, Weston A. Cyp3a4 polymorphisms–potential risk factors for breast and prostate cancer: a huge review. Am J Epidemiol. 2004;160:825–41.PubMedCrossRefGoogle Scholar
  32. 32.
    Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modification of clinical presentation of prostate tumors by a novel genetic variant in cyp3a4. Journal of the National Cancer Institute. 1998;90:1225–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Paris PL, Kupelian PA, Hall JM, Williams TL, Levin H, Klein EA, Casey G, Witte JS. Association between a cyp3a4 genetic variant and clinical presentation in African-American prostate cancer patients. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1999;8:901–5.Google Scholar
  34. 34.
    Bolufer P, Collado M, Barragan E, Calasanz MJ, Colomer D, Tormo M, Gonzalez M, Brunet S, Batlle M, Cervera J, Sanz MA. Profile of polymorphisms of drug-metabolising enzymes and the risk of therapy-related leukaemia. Br J Haematol. 2007;136:590–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Kadlubar FF, Berkowitz GS, Delongchamp RR, Wang C, Green BL, Tang G, Lamba J, Schuetz E, Wolff MS. The cyp3a4*1b variant is related to the onset of puberty, a known risk factor for the development of breast cancer. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2003;12:327–31.Google Scholar
  36. 36.
    Krishna DR, Shekar MS. Cytochrome p450 3a: Genetic polymorphisms and inter-ethnic differences. Methods and findings in experimental and clinical pharmacology. 2005;27:559–67.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2012

Authors and Affiliations

  • Li-Ping Zhou
    • 1
  • Fan Yao
    • 2
    Email author
  • Hong Luan
    • 1
  • Yin-Ling Wang
    • 1
  • Xi-Hua Dong
    • 1
  • Wen-Wen Zhou
    • 1
  • Qi-Hui Wang
    • 1
  1. 1.Department of Laboratory MedicineThe First Hospital of China Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Breast SurgeryThe First Hospital of China Medical UniversityHeping DistrictPeople’s Republic of China

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