Skip to main content

Advertisement

SpringerLink
Log in

ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study was to determine the significance of three most common single-nucleotide polymorphisms (SNPs) of ABCB1 gene in the development of colorectal cancer and to estimate the influence of these SNPs to surviving patients' treatment combination adjuvant therapy 5-fluorouracil/leucovorin. Haplotype structure of ABCB1 was analysed, and degree of linkage disequilibrium (LD) between SNPs of ABCB1 was estimated.

Materials and methods

Tumour specimens of 95 patients with colorectal cancer and blood samples of 95 healthy cases were studied. Genotyping of ABCB1 gene was performed by automated sequencing or polymerase chain reaction-restriction fragment length polymorphism method. Comparison of frequencies of alleles/genotypes/haplotypes between the studied group (colorectal cancer samples) and the control group (blood samples) were analysed. These results were correlated with the surviving patients after treatment of adjuvant chemotherapy.

Results

Significant differences in ABCB1 1236C>T (p = 0.00043) and ABCB1 2677G>T/A (p = 0.04) genotype distribution and T1236 allele distribution (CT1236 or TT1236 vs CC1236; p = 0.0499, OR = 0.55, Fi–Yule coefficient = 0.14) were found. A strong LD between ABCB1 1236C>T and ABCB1 2677G>T/A SNPs (D′ = 0.621, r 2 = 0.318) was detected. All SNPs were located in one haplotype block. There were significant differences in haplotype distributions between colorectal cancer patients and healthy population (p = 0.03). Significant differences in survival probability of colorectal cancer patients' treatment chemotherapy according to allele of ABCB1 3435C>T was observed. Survival probability of patients with wild-type C3435 allele were higher than among patients without this allele (p = 0.04572).

Conclusions

These results suggested that three studied SNPs of ABCB1 were located in one haplotype block. Differences in ABCB1 1236C>T and ABCB1 2677G>T/A genotypes and T1236 allele distribution between investigated populations indicate significant impact of these SNPs on risk of development of colorectal cancer. Polymorphism ABCB1 3435C>T may be a prediction marker of cancer chemotherapy effectiveness. Differences in haplotype distributions between colorectal cancer patients and healthy population suggested that other potential SNPs, especially in regulatory region of ABCB1 gene, may influence P-glycoprotein expression and function.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113

    Article  PubMed  CAS  Google Scholar 

  2. Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I, Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annu Rev Pharmacol Toxicol 39:361–398

    Article  PubMed  CAS  Google Scholar 

  3. Gottesman MM, Pastan I, Ambudkar SV (1996) P-glycoprotein and multidrug resistance. Curr Opin Genet Dev 6:610–617

    Article  PubMed  CAS  Google Scholar 

  4. Marzolini C, Paus E, Buclin T, Kim RB (2004) Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther 75:13–33

    Article  PubMed  CAS  Google Scholar 

  5. Sakaeda T, Nakamura T, Okumura K (2003) Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs. Pharmacogenomics 4:397–410

    Article  PubMed  CAS  Google Scholar 

  6. Tanigawara Y (2000) Role of P-glycoprotein in drug disposition. Ther Drug Monit 22:137–140

    Article  PubMed  CAS  Google Scholar 

  7. Terao T, Hisanaga E, Sai Y, Tamai I, Tsuji A (1996) Active secretion of drugs from the small intestinal epithelium in rats by P-glycoprotein functioning as an absorption barrier. J Pharm Pharmacol 48:1083–1089

    PubMed  CAS  Google Scholar 

  8. Kemp Z, Thirlwell C, Sieber O, Silver A, Tomlinson I (2004) An update on the genetics of colorectal cancer. Hum Mol Genet 13:R177–185

    Article  PubMed  CAS  Google Scholar 

  9. Potocnik U, Ravnik-Glavac M, Golouh R, Glavac D (2002) Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers. J Med Genet 39:340–346

    Article  PubMed  CAS  Google Scholar 

  10. Kroetz DL, Pauli-Magnus C, Hodges LM, Huang CC, Kawamoto M, Johns SJ, Stryke D, Ferrin TE, DeYoung J, Taylor T, Carlson EJ, Herskowitz I, Giacomini KM, Clark AG, Pharmacogenetics of Membrane Transporters Investigators (2003) Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 13:481–494 Erratum in: Pharmacogenetics 13:701

    Article  PubMed  CAS  Google Scholar 

  11. Cascorbi I, Gerloff T, Johne A, Meisel C, Hoffmeyer S, Schwab M, Schaeffeler E, Eichelbaum M, Brinkmann U, Roots I (2001) Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther 69:169–174

    Article  PubMed  CAS  Google Scholar 

  12. 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 U S A 97:3473–3478

    Article  PubMed  CAS  Google Scholar 

  13. Sakaeda T (2005) MDR1 genotype-related pharmacokinetics: fact or fiction? Drug Metab Pharmacokinet 20:391–414

    Article  PubMed  CAS  Google Scholar 

  14. Sakaeda T, Nakamura T, Okumura K (2004) Pharmacogenetics of drug transporters and its impact on the pharmacotherapy. Curr Top Med Chem 4:1385–1398

    Article  PubMed  CAS  Google Scholar 

  15. Tang K, Ngoi SM, Gwee PC, Chua JM, Lee EJ, Chong SS, Lee CG (2002) Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics 12:437–450

    Article  PubMed  CAS  Google Scholar 

  16. Kim RB, Leake B, Choo E, Dresser GK, Kubba SV, Schwarz UI, Taylor A, Xie H-G, Stein CM, Wood AJJ, McKinsey J, Schuetz EG, Schuetz JD, Wilkinson GR (2000) Drug Metab Rev 32, Abstract 199

  17. 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 13:1847–1854

    Article  PubMed  CAS  Google Scholar 

  18. Jamroziak K, Młynarski 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 72:314–321

    Article  PubMed  CAS  Google Scholar 

  19. 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 23:2735–2740

    PubMed  CAS  Google Scholar 

  20. 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 21:126–132

    Article  PubMed  CAS  Google Scholar 

  21. 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 61:389–394

    Article  PubMed  CAS  Google Scholar 

  22. Osswald E, Johne A, Laschinski G, Arjomand-Nahad F, Malzahn U, Kirchheiner J, Gerloff T, Meisel C, Mrozikiewicz PM, Chernov J, Roots I, Köpke K (2007) Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers. Eur J Clin Pharmacol 63:9–16

    Article  PubMed  CAS  Google Scholar 

  23. Gill S, Sinicrope FA (2005) Colorectal cancer prevention: is an ounce of prevention worth a pound of cure? Semin Oncol 32:24–34

    Article  PubMed  CAS  Google Scholar 

  24. Mochida Y, Taguchi K, Taniguchi S, Tsuneyoshi M, Kuwano H, Tsuzuki T, Kuwano M, Wada M (2003) The role of P-glycoprotein in intestinal tumorigenesis: disruption of mdr1a suppresses polyp formation in Apc(Min/+) mice. Carcinogenesis 24:1219–1224

    Article  PubMed  CAS  Google Scholar 

  25. Kankesan J, Vanama R, Yusuf A, Thiessen JJ, Ling V, Rao PM, Rajalakshmi S, Sarma DS (2004) Effect of PSC 833, an inhibitor of P-glycoprotein on N-methyl-N-nitrosourea induced mammary carcinogenesis in rats. Carcinogenesis 25:425–430

    Article  PubMed  CAS  Google Scholar 

  26. Kankesan J, Yusuf A, Laconi E, Vanama R, Bradley G, Thiessen JJ, Ling V, Rao PM, Rajalakshmi S, Sarma DS (2003) Effect of PSC 833, an inhibitor of P-glycoprotein, on 1, 2-dimethylhydrazine-induced liver carcinogenesis in rats. Carcinogenesis 24:1977–1984

    Article  PubMed  CAS  Google Scholar 

  27. Tanabe M, Ieiri I, Nagata N, Inoue K, Ito S, Kanamori Y, Takahashi M, Kurata Y, Kigawa J, Higuchi S, Terakawa N, Otsubo K (2001) Expression of P-glycoprotein in human placenta: relation to genetic polymorphism of the multidrug resistance (MDR)-1 gene. J Pharmacol Exp Ther 297:1137–1143

    PubMed  CAS  Google Scholar 

  28. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68:978–989

    Article  PubMed  CAS  Google Scholar 

  29. Slatkin M, Excoffier L (1996) Testing for linkage disequilibrium in genotypic data using the Expectation-Maximization algorithm. Heredity 76:377–383

    Article  PubMed  Google Scholar 

  30. 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 134:317–322

    Article  PubMed  CAS  Google Scholar 

  31. Ho GT, Moodie FM, Satsangi J (2003) Multidrug resistance 1 gene (Pglycoprotein 170): an important determinant in gastrointestinal disease? Gut 52:759–766

    Article  PubMed  CAS  Google Scholar 

  32. Ameyaw MM, Regateiro F, Li T, Liu X, Tariq M, Mobarek A, Thornton N, Folayan GO, Githang'a J, Indalo A, Ofori-Adjei D, Price-Evans DA, McLeod HL (2001) MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 11:217–221

    Article  PubMed  CAS  Google Scholar 

  33. Schaeffeler E, Eichelbaum M, Brinkmann U, Penger A, Asante-Poku S, Zanger UM, Schwab M (2001) Frequency of C3435T polymorphism of MDR1 gene in African people. Lancet 358:383–384

    Article  PubMed  CAS  Google Scholar 

  34. Schoen RE (2000) Families at risk for colorectal cancer: risk assessment and genetic testing. J Clin Gastroenterol 31:114–120

    Article  PubMed  CAS  Google Scholar 

  35. Schwab M, SchaeVeler E, Marx C, Fromm MF, Kaskas B, Metzler J, Stange E, Herfarth H, Schoelmerich J, Gregor M, Walker S, Cascorbi I, Roots I, Brinkmann U, Zanger UM, Eichelbaum M (2003) Association between the C3435T MDR1 gene polymorphism and susceptibility for ulcerative colitis. Gastroenterology 124:26–33

    Article  PubMed  CAS  Google Scholar 

  36. Urcelay E, Mendoza JL, Martin MC, Mas A, Martinez A, Taxonera C, Fernandez-Arquero M, Diaz-Rubio M, de la Concha EG (2006) MDR1 gene: susceptibility in Spanish Crohn's disease and ulcerative colitis patients. InXamm Bowel Dis 12:33–37

    Article  Google Scholar 

  37. Gaikovitch E, Mrozikievicz P, Wagner F, Roots I (2004) Association of C3435T and G2677T/A polymorphisms of multidrug resistance gene with colorectal cancer risk. Clin Pharmacol Ther 75:17

    Article  Google Scholar 

  38. Saito K, Miyake S, Moriya H, Yamazaki M, Itoh F, Imai K, Kurosawa N, Owada E, Miyamoto A (2003) Detection of the four sequence variations of MDR1 gene using TaqMan MGB probe based real-time PCR and haplotype analysis in healthy Japanese subjects. Clin Biochem 36:511–518

    Article  PubMed  CAS  Google Scholar 

  39. Taniguchi S, Mochida Y, Uchiumi T, Tahira T, Hayashi K, Takagi K, Shimada M, Maehara Y, Kuwano H, Kono S, Nakano H, Kuwano M, Wada M (2003) Genetic polymorphism at the 5′ regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon. Mol Cancer Ther 2:1351–1359

    PubMed  CAS  Google Scholar 

  40. Rund D, Azar I, Shperling O (1999) A mutation in the promoter of the multidrug resistance gene (MDR1) in human hematological malignancies may contribute to the pathogenesis of resistant disease. Adv Exp Med Biol 457:71–75

    PubMed  CAS  Google Scholar 

  41. Colombo S, Soranzo N, Rotger M, Sprenger R, Bleiber G, Furrer H, Buclin T, Goldstein D, Decosterd L, Telenti A; Swiss HIV Cohort Study (2005) Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo. Pharmacogenet Genomics 15:599–608

    Article  Google Scholar 

  42. 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 183:28–34

    Article  PubMed  CAS  Google Scholar 

  43. Yamada T, Takaoka AS, Naishiro Y, Hayashi R, Maruyama K, Maesawa C, Ochiai A, Hirohashi S (2000) Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. Cancer Res 60:4761–4766

    PubMed  CAS  Google Scholar 

  44. Potocnik U, Ferkolj I, Glavac D, Dean M (2004) Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun 5:530–539

    Article  PubMed  CAS  Google Scholar 

  45. Sakaeda T, Nakamura T, Okumura K (2002) MDR1 genotype-related pharmacokinetics and pharmacodynamics. Biol Pharm Bull 25:1391–400

    Article  PubMed  CAS  Google Scholar 

  46. Zimprich F, Sunder-Plassmann R, Stogmann E, Gleiss A, Dal-Bianco A, Zimprich A, Plumer S, Baumgartner C, Mannhalter C (2004) Association of an ABCB1 gene haplotype with pharmacoresistance in temporal lobe epilepsy. Neurology 63:1087–1089

    PubMed  CAS  Google Scholar 

  47. Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, Ambudkar SV, Gottesman MM (2007) A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science 315:525–528

    Article  PubMed  CAS  Google Scholar 

  48. Smyth MJ, Krasovskis E, Sutton VR, Johnstone RW (1998) The drug efflux protein, P-glycoprotein, additionally protects drug-resistant tumor cells from multiple forms of caspase-dependent apoptosis. Proc Natl Acad Sci U S A 95:7024–7029

    Article  PubMed  CAS  Google Scholar 

  49. Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3:330–338

    Article  PubMed  CAS  Google Scholar 

  50. Coleman MP, Gatta G, Verdecchia A, Esteve J, Sant M, Storm H, Allemani C, Ciccolallo L, Santaquilani M, Berrino F, EUROCARE Working Group (2003) EUROCARE-3 summary: cancer survival in Europe at the end of the 20th century. Ann Oncol 14(Suppl 5):v128–149

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grant P05F 02628 from the State Committee for Scientific Research, Warsaw Poland and from the Medical University of Łódź 503-3015-2.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Biochemistry, Laboratory of Molecular Biology and Pharmacogenomics, Medical University of Lodz, Muszynskiego 1 Street, 90-151, Lodz, Poland

    Mariusz Panczyk, Ewa Balcerczak & Marek Mirowski

  2. Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland

    Sylwester Piaskowski

  3. Department of Haematology, Medical University of Lodz, Lodz, Poland

    Krzysztof Jamroziak

  4. Department of Pathology, Medical University of Lodz, Lodz, Poland

    Grażyna Pasz-Walczak

Authors
  1. Mariusz Panczyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ewa Balcerczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sylwester Piaskowski
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Krzysztof Jamroziak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Grażyna Pasz-Walczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marek Mirowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariusz Panczyk.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Panczyk, M., Balcerczak, E., Piaskowski, S. et al. ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis 24, 895–905 (2009). https://doi.org/10.1007/s00384-009-0724-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-009-0724-0

Keywords

Search

Navigation