MDR1 C3435T and C1236T Polymorphisms: Association with High-risk Childhood Acute Lymphoblastic Leukemia

  • Pongstaporn, Wanida (Pathobiology Unit, Department of Biomedical Science, Faculty of Science, Rangsit University) ;
  • Pakakasama, Samart (Department of Pediatrics, Ramathibodi Hospital, Faculty of Medicine, Mahidol University) ;
  • Chaksangchaichote, Panee (Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University) ;
  • Pongtheerat, Tanett (Biochemistry Unit, Department of Biomedical Science, Faculty of Science, Rangsit University) ;
  • Hongeng, Suradej (Department of Pediatrics, Ramathibodi Hospital, Faculty of Medicine, Mahidol University) ;
  • Permitr, Songsak (Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University)
  • Published : 2015.04.14


Background: MDR1, one of the most important drug-transporter genes, encodes P- glycoprotein (P-gp)-a transporter involved in protecting against xenobiotics and multi-drug resistance. The significance of the genetic background in childhood acute lymphoblastic leukemia (ALL) is not well understood. Materials and Methods: To evaluate whether C3435T and C1236T MDR1 polymorphisms are associated with the occurrence and outcome of ALL, 208 children with ALL (median age 5.0 yr) and 101 healthy Thai children were studied by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assay. Results: C3435T and C1236T MDR1 polymorphism are significantly associated with the high-risk group (OR= 2.6, 95%CI =1.164-5.808; P=0.028 and OR= 2.231, 95%CI =1.068-4.659; p=0.047, respectively), indicating that both may be candidates for molecular markers in the high-risk group of ALL.


Acute lymphoblastic leukemia;MDR1 polymorphism;high-risk group;Thailand


Supported by : Research Institute of Rangsit University


  1. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003). P-glycoprotein: from genomics to mechanism. Oncogene, 22, 7468-5.
  2. Bekas-Kayan K, Kucukhuseyin O, Karagoz G, et al (2012). Is the MDR1 C3435T polymorphism responsible for oral mucositis in children with acute lymphoblastic leukemia. Asian Pac J Cancer Prev, 13, 15251-5.
  3. Borst P, Elferink RO (2002). Mammalian ABC transporters in health and disease. Annu Rev Biochem, 71, 537-592.
  4. Claus R. Bartram, Andre Schrauder, Rolf Kohler, Martin Schrappe (2012). Acute lymphoblastic leukemia in children: treatment planning via minimal residual disease assessment. Dtsch Arztebl Int, 109, 652-8
  5. Dong HJ, Miao KR, Qiao C, et al (2011). Polymorphisms and haplotypes in multidrug resistance 1 gene are not associated with chronic lymphocytic leukemia in Chinese population. Leukemia Lymphoma, 52, 1003-9.
  6. Fung KL, Gottesman MM (2009). A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function. Biochim Biophys Acta, 1794, 860-71.
  7. Hattori H, Suminoe A, Wada M, et al (2007). Regulatory polymorphisms of multidrug resistance 1 (MDR1) gene are associated with the development of childhood acute lymphoblastic leukemia. Leuk Res, 31, 1633-1640.
  8. He T, Mo A, Zhang K, Liu L (2013). ABCB1/MDR1 polymorphism and colorectal cancer risk: a meta-analysis of case-control studies. Colorectal Dis, 15, 12-18.
  9. Hoffmeyer S, Burk O, von Richter O, et al (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, 97, 3473-8.
  10. Hitzl M, Drescher S, van der Kuip H, et al (2001). The C3435T mutation in the human MDR1 gene is associated with altered efflux of the P-glycoprotein substrate rhodamine 123 from CD56+ natural killer cells. Pharmacogenetics, 11, 293-8.
  11. Jamroziak K, Robak T (2004). Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies. Hematology, 9, 91-105.
  12. Jamroziak K, Mlynarski W, Balcerczak E, et al (2004). Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol, 72, 314-321.
  13. Kerb R (2006). Implications of genetic polymorphisms in drug transporters for pharmacology. Cancer letters, 234, 4-33.
  14. Kim RB., Leake BF., Choo EF, et al (2001). Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther, 70, 189-99.
  15. Komar AA (2007). Silent SNPs: impact on gene function and phenotype. Pharmacogenomics, 8, 1075-80.
  16. Kreile M, Rots D, Plekuse L, et al (2014). Lack of association between polymorphism in genes MTHFR and MDR1 with the risk of childhood acute lymphoblastic leulemia. Asian Pacific J Cancer Prev, 15, 9707-11
  17. Kurzawski M, Drozdzik M, Suchy J, et al (2005). Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Euro J Clinical Pharmacology, 61, 389-94.
  18. Lavedriere C, Chiasson S, Costea I, Moghrabi A, Krajinovic M (2002). Polymorphisms G80A in in the reduced folate carrier gene and its relationship to methotrexate plasma levels and outcome of childhood lymphoblastic leukaemia. Blood, 100, 3832-4.
  19. Leal-Uqarte E, Gutierrez-Angulo M, Macias_Gomez NM, et al (2008). MDR1 C3435T polymorphism in Mexican children with acute lymphoblastic leukemia and in healthy individuals. Hum Biol, 80, 449-455.
  20. Martin Belson, Beverely Kingsley, Adrianne Holmes (2007). Risk factors for acute leukemia in children: A review. Environmental Health Perspectives, 115, 141-5.
  21. McLeod HL, Krynetski EY, Relling MV, Evans WE (2000). Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukaemia. Leukemia, 14, 567-2.
  22. Miler SA, Dykes DD, Polsky HF (1988). Simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res, 16, 1215.
  23. Nakamura T, Sakaeda T, Horinouchi M, et al (2002). Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther, 71, 297-303.
  24. Ozdmir S, Uladag A, Silan F, et al (2013). Possible roles of xenobiotic transporter P-glycoproteins encoded by the MDR1 3435 C>T gene polymorphism in differentiated thyroid cancer. Asian Pac J Cancer Prev, 14, 3213-7.
  25. Pui CH, Relling MV, Downing JR (2004). Acute lymphoblastic leukemia. N Engl J Med, 350, 1535-48.
  26. Rao DN, Anuradha C, Visnupriya S, et al (2010). Association of an MDR1 gene (C3435T) polymorphism with acute leukemia in India. Asian Pac J Cancer Prev, 11, 1063-6.
  27. Ren YQ, Han JQ, Cao JB, LiSX, Fan GR (2012). Association of MDR1 gene polymorphisms with susceptibility to hepatocellular carcinoma in Chinese population. Asian Pac J Cancer Prev, 13, 5451-4.
  28. Ryu HC, Kwon HY, Choi IK, Rhee DK (2006). Analysis of single nucleotide polymorphisms and haplotype linkage of human ABCB1 (MDR1) gene in Korean. Arch Pharam Res, 29, 1132-9.
  29. Sammanian S, Mahjoubi F, Mahjoubi B, Mirzaee R, Azizi R (2011). MDR1 gene polymorphisms: possible association with its expression and clincopathology characteristics in colorectal cancer patients. Asian Pac J Cancer Prev, 12, 3141-5.
  30. Semsei AF, Erdelyi DJ, Ungvari I, et al (2008). Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukemia. Leuk Res, 32, 1214-20.
  31. Sheng X, Zhang L, Tong N (2012). MDR1 C3435T polymorphism and cancer risk: a meta-analysis based on 39 case-control studies. Mol Biol Rep, 39, 7237-49.
  32. Smith M, Arthur D, Camitta B, et al (1996). Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol, 14, 18-24.
  33. Taheri M., Mahjoubi F., Omranipour R (2010). Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Genet Mol Res, 12, 34-40.
  34. Ullah MF (2008). Cancer multidrug resistance (MDR): A major impediment to effective chemotherapy. Asian Pac J Cancer Prev, 9, 1-6.
  35. Urayama KY, Wiencke JK, Buffer PA, et al (2007). MDR1 gene varients, indoor insecticide expourse, and the risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev, 16, 1172-7.
  36. Wang J, Wang B, Bi J, Li K, Di J (2012). MDR1 gene C3435T polymorphism and cancer risk: a meta-analysis of 34 case-control studies. Cancer Res Clin Oncol, 138, 979-89.
  37. Wei HB, Hu J, Shang LH, et al (2012). A meta-analytic review of ERCC1/MDR1 polymorphism and chemosensitivity to platinum in patients with advanced non-small cell lung cancer. Chin Med J, 125, 2902-7.
  38. Wu DD, Zhang JX, Li J, Dong WG (2014). Lack of association of the MDR1 C3435T polymorphism with susceptibility to gastric cancer and peptic ulcer: A systematic review and meta-analysis. Asian Pac J Cancer Prev, 15, 3021-3027.
  39. Yan PW, Huang XE, Yan F, Xu L, Jiang Y (2011). Influence of MDR1 gene codon 3435 polymorphisms on outcome of platinum based chemotherapy for advanced non small cell lung cancer. Asian Pac J Cancer Prev, 12, 2291-4.
  40. Zhai X, Wang H, Zhu X, et al (2012). Gene polymorphisms of ABC transporters are associated with clinical outcomes in children with acute lymphoblastic leukemia. Arch Med Sci, 8, 659-71.

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