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MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case–control studies

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Abstract

Multidrug resistance 1 (MDR1) gene encodes the ATP-dependent cellular efflux pump P-glycoprotein (P-gp) which efflux of a variety of substances across the membrane. P-gp could serve a role in cancer etiology based on its physiological role of protecting cells from xenobiotics or metabolites. The C3435T (rs1045642) polymorphism of the MDR1 gene which could influence the P-gp expression and function have been implicated in the cancer risk. However, the results from the published studies on the association between this polymorphism and cancer risk are conflicting. To drive a more precise estimation of this association, we performed a meta-analysis of 39 case–control studies, including a total of 9,265 cancer cases and 13,502 controls. We used odds ratios (ORs) with their 95% confidence intervals (CIs) to assess the strength of the association. Overall, individuals with the MDR1 3435TT genotype were associated with an increased cancer risk than those with the CC (OR = 1.29, 95% CI: 1.10–1.51) or CT/CC (OR = 1.18, 95% CI: 1.04–1.34) genotypes, similar to the CT or CT/TT compared with the CC genotype. In the stratified analyses, the increased risks were more pounced among hematologic malignances (OR = 1.27, 95% CI: 1.10–1.46, P heterogeneity = 0.415), breast cancer (1.42, 1.04–1.94, 0.018), renal cancer (1.77, 1.28–2.46, 0.307), Caucasians (1.21, 1.07–1.38, 0.000) and population-based studies (1.20, 1.05–1.36, 0.000) in a dominant model. The results suggested that the MDR1 C3435T polymorphism may contribute to cancer risk.

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References

  1. Pharoah PD, Dunning AM, Ponder BA, Easton DF (2004) Association studies for finding cancer-susceptibility genetic variants. Nat Rev Cancer 4(11):850–860

    Article  PubMed  CAS  Google Scholar 

  2. Hoeijmakers JH (2001) Genome maintenance mechanisms for preventing cancer. Nature 411(6835):366–374

    Article  PubMed  CAS  Google Scholar 

  3. Bodor M, Kelly EJ, Ho RJ (2005) Characterization of the human MDR1 gene. AAPS J 7(1):E1–E5

    Article  PubMed  Google Scholar 

  4. Allikmets R, Gerrard B, Hutchinson A, Dean M (1996) Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 5(10):1649–1655

    Article  PubMed  CAS  Google Scholar 

  5. Yamada O, Ozaki K, Furukawa T, Machida M, Wang YH, Motoji T, Mitsuishi T, Akiyama M, Yamada H, Kawauchi K, Matsuoka R (2011) Activation of STAT5 confers imatinib resistance on leukemic cells through the transcription of TERT and MDR1. Cell Signal 23(7):1119–1127

    Article  PubMed  CAS  Google Scholar 

  6. Johnstone RW, Ruefli AA, Smyth MJ (2000) Multiple physiological functions for multidrug transporter P-glycoprotein? Trends Biochem Sci 25(1):1–6

    Article  PubMed  CAS  Google Scholar 

  7. 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(10):693–704

    Article  PubMed  CAS  Google Scholar 

  8. 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(7):3473–3478

    Article  PubMed  CAS  Google Scholar 

  9. Rao DN, Anuradha C, Vishnupriya S, Sailaja K, Surekha D, Raghunadharao D, Rajappa S (2010) Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev 11(4):1063–1066

    PubMed  Google Scholar 

  10. 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(7):1847–1854

    Article  PubMed  CAS  Google Scholar 

  11. 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(5):314–321

    Article  PubMed  CAS  Google Scholar 

  12. 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(5–6):389–394

    Article  PubMed  CAS  Google Scholar 

  13. 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(2):85–90

    Article  PubMed  Google Scholar 

  14. 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(12):2850–2857

    Article  PubMed  CAS  Google Scholar 

  15. Jamroziak K, Balcerczak E, Smolewski P, Robey RW, Cebula B, Panczyk M, Kowalczyk M, Szmigielska-Kaplon A, Mirowski M, Bates SE, Robak T (2006) MDR1 (ABCB1) gene polymorphism C3435T is associated with P-glycoprotein activity in B-cell chronic lymphocytic leukemia. Pharmacol Rep 58(5):720–728

    PubMed  CAS  Google Scholar 

  16. Jamroziak K, Balcerczak E, Cebula B, Janus A, Mirowski M, Robak T (2006) 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(5):707–711

    Article  PubMed  CAS  Google Scholar 

  17. 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(8):774–779

    Article  PubMed  CAS  Google Scholar 

  18. 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(2):127–136

    Article  PubMed  CAS  Google Scholar 

  19. 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(6):1172–1177

    Article  PubMed  CAS  Google Scholar 

  20. 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(6):1287–1293

    Article  PubMed  CAS  Google Scholar 

  21. 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(12):1633–1640

    Article  PubMed  CAS  Google Scholar 

  22. Turgut S, Yaren A, Kursunluoglu R, Turgut G (2007) MDR1 C3435T polymorphism in patients with breast cancer. Arch Med Res 38(5):539–544

    Article  PubMed  CAS  Google Scholar 

  23. 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(10):1678–1682

    Article  PubMed  CAS  Google Scholar 

  24. 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(1):9–16

    Article  PubMed  CAS  Google Scholar 

  25. 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(3):728–731

    Article  PubMed  CAS  Google Scholar 

  26. 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(1):56–65

    Article  PubMed  CAS  Google Scholar 

  27. Sam SS, Thomas V, Sivagnanam K, Reddy KS, Surianarayanan G, Chandrasekaran A (2007) ABCB1 genetic polymorphism and risk of upper aero digestive tract cancers among smokers, tobacco chewers and alcoholics in an Indian population. Pharmacogenet Genomics 17(10):861–866

    Article  PubMed  CAS  Google Scholar 

  28. 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(8):1214–1220

    Article  PubMed  CAS  Google Scholar 

  29. 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(4):449–455

    Article  PubMed  Google Scholar 

  30. 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(7–8):301–304

    Article  PubMed  CAS  Google Scholar 

  31. 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(3):317–322

    Article  PubMed  CAS  Google Scholar 

  32. 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(1):28–34

    Article  PubMed  CAS  Google Scholar 

  33. 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(2):332–335

    Article  PubMed  CAS  Google Scholar 

  34. Rocha V, Porcher R, Fernandes JF, Filion A, Bittencourt H, Silva W Jr, Vilela G, Zanette DL, Ferry C, Larghero J, Devergie A, Ribaud P, Skvortsova Y, Tamouza R, Gluckman E, Socie G, Zago MA (2009) Association of drug metabolism gene polymorphisms with toxicities, graft-versus-host disease and survival after HLA-identical sibling hematopoietic stem cell transplantation for patients with leukemia. Leukemia 23(3):545–556

    Article  PubMed  CAS  Google Scholar 

  35. Andersen V, Ostergaard M, Christensen J, Overvad K, Tjonneland A, Vogel U (2009) 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 9:407

    Article  PubMed  Google Scholar 

  36. Panczyk M, Balcerczak E, Piaskowski S, Jamroziak K, Pasz-Walczak G, Mirowski M (2009) ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis 24(8):895–905

    Article  PubMed  Google Scholar 

  37. 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(3):161–165

    Article  PubMed  CAS  Google Scholar 

  38. 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(5):259–263

    Article  PubMed  CAS  Google Scholar 

  39. Drain S, Catherwood MA, Orr N, Galligan L, Rea IM, Hodkinson C, Drake MB, Kettle PJ, Morris TC, Alexander HD (2009) ABCB1 (MDR1) rs1045642 is associated with increased overall survival in plasma cell myeloma. Leuk Lymphoma 50(4):566–570

    Article  PubMed  CAS  Google Scholar 

  40. 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(6):1425–1433

    Article  PubMed  CAS  Google Scholar 

  41. Penna G, Allegra A, Alonci A, Aguennouz M, Garufi A, Cannavo A, Gerace D, Alibrandi A, Musolino C (2010) MDR-1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia: an impact on susceptibility and prognosis. Med Oncol 28(4):1549–1554

    Article  PubMed  Google Scholar 

  42. Khedri A, Nejat-Shokouhi A, Salek R, Esmaeili H, Mokhtarifar A, Entezari Heravi R, Tatari F, Behravan J, Miladpour B, Omidvar Tehrani S (2011) Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population. Mol Biol Rep 38(5):2939–2943

    Article  PubMed  CAS  Google Scholar 

  43. Taheri M, Mahjoubi F, Omranipour R (2010) Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Genet Mol Res 9(1):34–40

    Article  PubMed  CAS  Google Scholar 

  44. Chang H, Rha SY, Jeung HC, Im CK, Noh SH, Kim JJ, Chung HC (2010) Association of the ABCB1 3435C>T polymorphism and treatment outcomes in advanced gastric cancer patients treated with paclitaxel-based chemotherapy. Oncol Rep 23(1):271–278

    PubMed  CAS  Google Scholar 

  45. 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(3):317–321

    Article  PubMed  CAS  Google Scholar 

  46. Abbas S, Bechmann L, Chang-Claude J, Hein R, Kropp S, Parthimos M, Dunnebier T, Hamann U, Brors B, Eils R, Zapatka M (2010) Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat 120(3):727–736

    Article  CAS  Google Scholar 

  47. 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(1):62–69

    Article  PubMed  CAS  Google Scholar 

  48. Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22(4):719–748

    PubMed  CAS  Google Scholar 

  49. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188

    Article  PubMed  CAS  Google Scholar 

  50. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634

    Article  PubMed  CAS  Google Scholar 

  51. Komar AA (2007) Silent SNPs: impact on gene function and phenotype. Pharmacogenomics 8(8):1075–1080

    Article  PubMed  CAS  Google Scholar 

  52. Fung KL, Gottesman MM (2009) A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta 1794(5):860–871

    PubMed  CAS  Google Scholar 

  53. 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(1):40–45

    Article  PubMed  CAS  Google Scholar 

  54. Lu PH, Wei MX, Yang J, Liu X, Tao GQ, Shen W, Chen MB (2011) Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a meta-analysis. Breast Cancer Res Treat 125(2):537–543

    Article  PubMed  Google Scholar 

  55. Wang J, Wang B, Bi J (2011) Significant association between ABCB1 gene C3435T polymorphism and breast cancer risk. Breast Cancer Res Treat 126(3):815–817

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was partly supported by National Natural Science Foundation of China (30872084, 30972444, and 81102089), the Key Program of Natural Science Foundation of Jiangsu Province (BK2010080), Natural Science Foundation of Jiangsu Province (BK2011773, and BK2011775), the Key Program for Basic Research of Jiangsu Provincial Department of Education (08KJA330001, and 11KJB330002), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Public Health and Preventive Medicine).

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Authors and Affiliations

  1. State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, China

    Xiaojing Sheng & Zhengdong Zhang

  2. Department of Occupational Medicine and Environmental Health, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Cancer Center, Nanjing Medical University, Nanjing, 210029, China

    Xiaojing Sheng, Na Tong, Dewei Luo, Min Xu & Zhengdong Zhang

  3. Department of Pediatrics, The Third Affiliated Hospital of Nanjing Medical University, Yizheng, 211900, China

    Limei Zhang

  4. Department of Molecular & Genetic Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, 210029, China

    Meilin Wang & Zhengdong Zhang

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  1. Xiaojing Sheng
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  2. Limei Zhang
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  3. Na Tong
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  4. Dewei Luo
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  5. Meilin Wang
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  6. Min Xu
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Correspondence to Zhengdong Zhang.

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Xiaojing Sheng, Limei Zhang and Na Tong have contributed equally to this work.

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Sheng, X., Zhang, L., Tong, N. et al. MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case–control studies. Mol Biol Rep 39, 7237–7249 (2012). https://doi.org/10.1007/s11033-012-1554-7

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