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MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case–control studies

  • Jun WangEmail author
  • Baocheng Wang
  • Jingwang Bi
  • Kainan Li
  • Jianshi Di
Original Paper

Abstract

Background

P-glycoprotein, the product of the MDR1 gene, is a transmembrane active efflux pump for a variety of environmental toxins and xenobiotics. Epidemiological studies have evaluated the association between MDR1 C3435T polymorphism and cancer susceptibility. However, published data are still inconclusive.

Methods

To derive a more precise assessment of this relevance, we performed a meta-analysis, up to September 2010, of 5,196 cases with different cancer types and 6,827 controls from 34 published case–control studies. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for MDR1 C3435T polymorphism and cancer were estimated using fixed- and random-effects models when appropriate.

Results

The overall results suggested that the variant was associated with a moderately increased cancer risk in all comparison models tested (OR = 1.26, 95% CI: 1.06–1.50 for TT vs. CC; OR = 1.19, 95% CI: 1.04–1.37 for CT vs. CC; OR = 1.15, 95% CI: 1.01–1.32 for recessive model; OR = 1.21, 95% CI: 1.06–1.38 for domain model, and OR = 1.14, 95% CI: 1.04–1.26 for allele contrast). In the subgroup analysis by cancer types, significant associations were found in breast cancer (OR = 1.66, 95% CI: 1.24–2.21 for TT vs. CC; OR = 1.44, 95% CI: 1.14–1.82 for recessive model; OR = 1.41, 95% CI: 1.10–1.81 for domain model; and OR = 1.31, 95% CI: 1.13–1.52 for allele contrast) and renal cancer (OR = 1.99, 95% CI: 1.37–2.90 for TT vs. CC; OR = 1.74, 95% CI: 1.25–2.42 for domain model; OR = 1.43, 95% CI: 1.09–1.88 for recessive model; and OR = 1.40, 95% CI: 1.17–1.68 for allele contrast). However, no significant associations were found in colorectal cancer, gastric cancer, and acute lymphoblastic leukemia for all genetic models. In the ethnicity subgroup analysis, a significant association with cancer among Caucasians was found under the dominant model, homozygote comparison, CT versus CC comparison, and allele comparison.

Conclusions

In summary, this meta-analysis suggests that the MDR1 C3435T polymorphism is associated with cancer susceptibility, increasing the risk of breast and renal cancer.

Keywords

Cancer susceptibility Polymorphism MDR1 Meta-analysis 

Notes

Acknowledgments

This study was supported by the National Nature Science Foundation of China (30901788) and Shandong Provincial Nature Science Foundation (ZR2010HQ038 and ZR2010HM059).

Conflict of interest

The authors declare no conflict of interest.

References

  1. Andersen V, Agerstjerne L, Jensen D, Ostergaard M, Saebo M, Hamfjord J, Kure E, Vogel U (2009a) The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study. BMC Med Genet 10:18PubMedCrossRefGoogle Scholar
  2. Andersen V, Ostergaard M, Christensen J, Overvad K, Tjonneland A, Vogel U (2009b) Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study. BMC Cancer 9:407PubMedCrossRefGoogle Scholar
  3. Bae SY, Choi SK, Kim KR, Park CS, Lee SK, Roh HK, Shin DW, Pie JE, Woo ZH, Kang JH (2006) Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans. Cancer Sci 97:774–779PubMedCrossRefGoogle Scholar
  4. Breier A, Barancik M, Sulova Z, Uhrik B (2005) P-glycoprotein–implications of metabolism of neoplastic cells and cancer therapy. Curr Cancer Drug Targets 5:457–468PubMedCrossRefGoogle Scholar
  5. Chen S, Huo X, Lin Y, Ban H, Li W, Zhang B, Au WW, Xu X (2010) Association of MDR1 and ERCC1 polymorphisms with response and toxicity to cisplatin-based chemotherapy in non-small-cell lung cancer patients. Int J Hyg Environ Health 213:140–145PubMedCrossRefGoogle Scholar
  6. Cizmarikova M, Wagnerova M, Schonova L, Habalova V, Kohut A, Linkova A, Sarissky M, Mojzis J, Mirossay L, Mirossay A (2010) MDR1 (C3435T) polymorphism: relation to the risk of breast cancer and therapeutic outcome. Pharmacogenomics J 10:62–69PubMedCrossRefGoogle Scholar
  7. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  8. Drozdzik M, Mysliwiec K, Lewinska-Chelstowska M, Banach J, Drozdzik A, Grabarek J (2004) P-glycoprotein drug transporter MDR1 gene polymorphism in renal transplant patients with and without gingival overgrowth. J Clin Periodontol 31:758–763PubMedCrossRefGoogle Scholar
  9. Fung KL, Gottesman MM (2009) A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 1794:860–871PubMedGoogle Scholar
  10. Gemignani F, Landi S, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gaborieau V, Gioia-Patricola L, Bellini I, Barale R, Canzian F, Hall J, Boffetta P, Hung RJ, Brennan P (2007) Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes. Carcinogenesis 28:1287–1293PubMedCrossRefGoogle Scholar
  11. George J, Dharanipragada K, Krishnamachari S, Chandrasekaran A, Sam SS, Sunder E (2009) A single-nucleotide polymorphism in the MDR1 gene as a predictor of response to neoadjuvant chemotherapy in breast cancer. Clin Breast Cancer 9:161–165PubMedCrossRefGoogle Scholar
  12. Gervasini G, Carrillo JA, Garcia M, San Jose C, Cabanillas A, Benitez J (2006) Adenosine triphosphate-binding cassette B1 (ABCB1) (multidrug resistance 1) G2677T/A gene polymorphism is associated with high risk of lung cancer. Cancer 107:2850–2857PubMedCrossRefGoogle Scholar
  13. Haenisch S, Zimmermann U, Dazert E, Wruck CJ, Dazert P, Siegmund W, Kroemer HK, Warzok RW, Cascorbi I (2007) Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex. Pharmacogenomics J 7:56–65PubMedCrossRefGoogle Scholar
  14. Hattori H, Suminoe A, Wada M, Koga Y, Kohno K, Okamura J, Hara T, Matsuzaki A (2007) Regulatory polymorphisms of multidrug resistance 1 (MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia. Leuk Res 31:1633–1640PubMedCrossRefGoogle Scholar
  15. Henriquez-Hernandez LA, Murias-Rosales A, Hernandez Gonzalez A, Cabrera De Leon A, Diaz-Chico BN, Mori De Santiago M, Fernandez Perez L (2009) Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case-control study. Oncol Rep 22:1425–1433PubMedCrossRefGoogle Scholar
  16. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558PubMedCrossRefGoogle Scholar
  17. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A, Cascorbi I, Gerloff T, Roots I, Eichelbaum M, Brinkmann U (2000) Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA 97:3473–3478PubMedCrossRefGoogle Scholar
  18. Humeny A, Rodel F, Rodel C, Sauer R, Fuzesi L, Becker C, Efferth T (2003) MDR1 single nucleotide polymorphism C3435T in normal colorectal tissue and colorectal carcinomas detected by MALDI-TOF mass spectrometry. Anticancer Res 23:2735–2740PubMedGoogle Scholar
  19. Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, Mirowski M, Bodalski J, Robak T (2004) Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol 72:314–321PubMedCrossRefGoogle Scholar
  20. Jamroziak K, Balcerczak E, Cebula B, Janus A, Mirowski M, Robak T (2006a) No influence of 3435C>T ABCB1 (MDR1) gene polymorphism on risk of adult acute myeloid leukemia and P-glycoprotein expression in blast cells. Ther Drug Monit 28:707–711PubMedCrossRefGoogle Scholar
  21. Jamroziak K, Balcerczak E, Smolewski P, Robey RW, Cebula B, Panczyk M, Kowalczyk M, Szmigielska-Kaplon A, Mirowski M, Bates SE, Robak T (2006b) MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia. Pharmacol Rep 58:720–728PubMedGoogle Scholar
  22. Jamroziak K, Balcerczak E, Calka K, Piaskowski S, Urbanska-Rys H, Salagacka A, Mirowski M, Robak T (2009) Polymorphisms and haplotypes in the multidrug resistance 1 gene (MDR1/ABCB1) and risk of multiple myeloma. Leuk Res 33:332–335PubMedCrossRefGoogle Scholar
  23. Khedri A, Nejat-Shokouhi A, Salek R, Esmaeili H, Mokhtarifar A, Entezari Heravi R, Tatari F, Behravan J, Miladpour B, Omidvar Tehrani S (2010) Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population. Mol Biol Rep 38:2939–2943PubMedCrossRefGoogle Scholar
  24. Komoto C, Nakamura T, Sakaeda T, Kroetz DL, Yamada T, Omatsu H, Koyama T, Okamura N, Miki I, Tamura T, Aoyama N, Kasuga M, Okumura K (2006) MDR1 haplotype frequencies in Japanese and Caucasian, and in Japanese patients with colorectal cancer and esophageal cancer. Drug Metab Pharmacokinet 21:126–132PubMedCrossRefGoogle Scholar
  25. Krupoves A, Seidman EG, Mack D, Israel D, Morgan K, Lambrette P, Costea I, Deslandres C, Grimard G, Law L, Levy E, Amre DK (2009) Associations between ABCB1/MDR1 gene polymorphisms and Crohn’s disease: a gene-wide study in a pediatric population. Inflamm Bowel Dis 15:900–908PubMedCrossRefGoogle Scholar
  26. Kurzawski M, Drozdzik M, Suchy J, Kurzawski G, Bialecka M, Gornik W, Lubinski J (2005) Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol 61:389–394PubMedCrossRefGoogle Scholar
  27. Leal-Ugarte E, Gutierrez-Angulo M, Macias-Gomez NM, Peralta-Leal V, Duran-Gonzalez J, De La Luz Ayala-Madrigal M, Partida-Perez M, Barros-Nunez P, Ruiz-Diaz D, Moreno-Ortiz JM, Peregrina-Sandoval J, Meza-Espinoza JP (2008) MDR1 C3435T polymorphism in Mexican children with acute lymphoblastic leukemia and in healthy individuals. Hum Biol 80:449–455PubMedCrossRefGoogle Scholar
  28. Lee BI, Choi KY, Lee KM, Chung WC, Kim BW, Choi H, Cho SH, Kang HJ, Lee JS, Kim MS, Chae HS, Chun IS (2006) Is C3435T polymorphism of MDR1 related to inflammatory bowel disease or colorectal cancer in Korean? Korean J Gastroenterol 47:22–29PubMedGoogle Scholar
  29. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748PubMedGoogle Scholar
  30. Miller KL, Kelsey KT, Wiencke JK, Moghadassi M, Miike R, Liu M, Wrensch M (2005) The C3435T polymorphism of MDR1 and susceptibility to adult glioma. Neuroepidemiology 25:85–90PubMedCrossRefGoogle Scholar
  31. Mrozikiewicz PM, Seremak-Mrozikiewicz A, Semczuk A, Landt O, Breborowicz GH, Drews K (2007) The significance of C3435T point mutation of the MDR1 gene in endometrial cancer. Int J Gynecol Cancer 17:728–731PubMedCrossRefGoogle Scholar
  32. Mutoh K, Mitsuhashi J, Kimura Y, Tsukahara S, Ishikawa E, Sai K, Ozawa S, Sawada J, Ueda K, Katayama K, Sugimoto Y (2006) A T3587G germ-line mutation of the MDR1 gene encodes a nonfunctional P-glycoprotein. Mol Cancer Ther 5:877–884PubMedCrossRefGoogle Scholar
  33. Nordgard SH, Ritchie MD, Jensrud SD, Motsinger AA, Alnaes GI, Lemmon G, Berg M, Geisler S, Moore JH, Lonning PE, Borresen-Dale AL, Kristensen VN (2007) ABCB1 and GST polymorphisms associated with TP53 status in breast cancer. Pharmacogenet Genomics 17:127–136PubMedCrossRefGoogle Scholar
  34. Ohsawa M, Ikura Y, Fukushima H, Shirai N, Sugama Y, Suekane T, Hirayama M, Hino M, Ueda M (2005) Immunohistochemical expression of multidrug resistance proteins as a predictor of poor response to chemotherapy and prognosis in patients with nodal diffuse large B-cell lymphoma. Oncology 68:422–431PubMedCrossRefGoogle Scholar
  35. Osswald E, Johne A, Laschinski G, Arjomand-Nahad F, Malzahn U, Kirchheiner J, Gerloff T, Meisel C, Mrozikiewicz PM, Chernov J, Roots I, Kopke K (2007) Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers. Eur J Clin Pharmacol 63:9–16PubMedCrossRefGoogle Scholar
  36. Paule B, Castagne V, Picard V, Saffroy R, Adam R, Guettier C, Farinotti R, Bonhomme-Faivre L (2010) MDR1 polymorphism role in patients treated with cetuximab and irinotecan in irinotecan refractory colorectal cancer. Med Oncol 27:1066–1072PubMedCrossRefGoogle Scholar
  37. Petrova DT, Nedeva P, Maslyankov S, Toshev S, Yaramov N, Atanasova S, Toncheva D, Oellerich M, von Ahsen N (2008) No association between MDR1 (ABCB1) 2677G>T and 3435C>T polymorphism and sporadic colorectal cancer among Bulgarian patients. J Cancer Res Clin Oncol 134:317–322PubMedCrossRefGoogle Scholar
  38. Potocnik U, Glavac D, Dean M (2008) Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability. Cancer Genet Cytogenet 183:28–34PubMedCrossRefGoogle Scholar
  39. Sabahi Z, Salek R, Heravi RE, Mosaffa F, Avanaki ZJ, Behravan J (2010) Association of gastric cancer incidence with MDR1 gene polymorphism in an ethnic Iranian population. Indian J Cancer 47:317–321PubMedCrossRefGoogle Scholar
  40. Semsei AF, Erdelyi DJ, Ungvari I, Kamory E, Csokay B, Andrikovics H, Tordai A, Csagoly E, Falus A, Kovacs GT, Szalai C (2008) Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukaemia. Leuk Res 32:1214–1220PubMedCrossRefGoogle Scholar
  41. Siegsmund M, Brinkmann U, Schaffeler E, Weirich G, Schwab M, Eichelbaum M, Fritz P, Burk O, Decker J, Alken P, Rothenpieler U, Kerb R, Hoffmeyer S, Brauch H (2002) Association of the P-glycoprotein transporter MDR1(C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol 13:1847–1854PubMedCrossRefGoogle Scholar
  42. Sugimoto M, Furuta T, Shirai N, Kodaira C, Nishino M, Yamade M, Ikuma M, Sugimura H, Ishizaki T, Hishida A (2008) MDR1 C3435T polymorphism has no influence on developing Helicobacter pylori infection-related gastric cancer and peptic ulcer in Japanese. Life Sci 83:301–304PubMedCrossRefGoogle Scholar
  43. Tahara T, Arisawa T, Shibata T, Hirata I, Nakano H (2007) Multi-drug resistance 1 polymorphism is associated with reduced risk of gastric cancer in the Japanese population. J Gastroenterol Hepatol 22:1678–1682PubMedCrossRefGoogle Scholar
  44. Taheri M, Mahjoubi F, Omranipour R (2010) Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Genet Mol Res 9:34–40PubMedCrossRefGoogle Scholar
  45. Tatari F, Salek R, Mosaffa F, Khedri A, Behravan J (2009) Association of C3435T single-nucleotide polymorphism of MDR1 gene with breast cancer in an Iranian population. DNA Cell Biol 28:259–263PubMedCrossRefGoogle Scholar
  46. Turgut S, Yaren A, Kursunluoglu R, Turgut G (2007) MDR1 C3435T polymorphism in patients with breast cancer. Arch Med Res 38:539–544PubMedCrossRefGoogle Scholar
  47. Urayama KY, Wiencke JK, Buffler PA, Chokkalingam AP, Metayer C, Wiemels JL (2007) MDR1 gene variants, indoor insecticide exposure, and the risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev 16:1172–1177PubMedCrossRefGoogle Scholar
  48. Uwai Y, Masuda S, Goto M, Motohashi H, Saito H, Okuda M, Nakamura E, Ito N, Ogawa O, Inui K (2004) Common single nucleotide polymorphisms of the MDR1 gene have no influence on its mRNA expression level of normal kidney cortex and renal cell carcinoma in Japanese nephrectomized patients. J Hum Genet 49:40–45PubMedCrossRefGoogle Scholar
  49. Wang D, Johnson AD, Papp AC, Kroetz DL, Sadee W (2005) Multidrug resistance polypeptide 1 (MDR1, ABCB1) variant 3435C>T affects mRNA stability. Pharmacogenet Genomics 15:693–704PubMedCrossRefGoogle Scholar
  50. Yan Q, Wajapeyee N (2010) Exploiting cellular senescence to treat cancer and circumvent drug resistance. Cancer Biol Ther 9:166–175PubMedCrossRefGoogle Scholar
  51. Yuan H, Li X, Wu J, Li J, Qu X, Xu W, Tang W (2008) Strategies to overcome or circumvent P-glycoprotein mediated multidrug resistance. Curr Med Chem 15:470–476PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Jun Wang
    • 1
    Email author
  • Baocheng Wang
    • 1
  • Jingwang Bi
    • 1
  • Kainan Li
    • 1
  • Jianshi Di
    • 1
  1. 1.Department of Oncology, General HospitalJinan Command of the People’s Liberation ArmyTianqiao District, JinanChina

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