Advertisement

No association between MDR1 (ABCB1) 2677G>T and 3435C>T polymorphism and sporadic colorectal cancer among Bulgarian patients

  • Darinka Todorova Petrova
  • Petya Nedeva
  • Svilen Maslyankov
  • Svetoslav Toshev
  • Nikolay Yaramov
  • Srebrena Atanasova
  • Draga TonchevaEmail author
  • Michael Oellerich
  • Nicolas von Ahsen
Original Paper

Abstract

Purpose

Variation in genetic factors together with xenobiotic exposure may result in increased risk of colorectal cancer. The P-glycoprotein (P-gp) is highly expressed in the apical membrane of enterocytes, where it pumps xenobiotics from the enterocytes back into the intestinal lumen. Thus, polymorphisms that reduce the activity of the MDR1 (ABCB1) efflux pump are potential risk factors for colorectal carcinogenesis. The aim of the present study is to genotype the MDR1 2677G>T (rs2032582) and 3435C>T (rs1045642) polymorphism in patients with colorectal cancer and controls and to identify a possible association between individual genetic variation and susceptibility to colorectal cancer.

Methods

In the present study, 146 Bulgarian patients with sporadic colorectal cancer and 160 healthy Bulgarian volunteers were evaluated for the two polymorphisms in MDR1. Polymorphisms were identified using rapid-cycle real-time amplification with allele-specific probes and subsequent melting curve analyses on a LightCycler™ (Roche Diagnostics, Mannheim, Germany).

Results

No differences were found between the frequencies of the two mutant alleles in the tumor tissue from the cases and lymphocytes from the controls [frequencies of 2677T: 43.5% in patients and 44.1% in controls; frequencies of 3435T: 48.3% in patients and 50.9% in controls (both P > 0.05)]. The MDR1 polymorphic sequence of the tumor tissue always matched that of normal intestinal tissue from the same patient. Consequently, genotyping of DNA from archived tumor tissues is a valid alternative to the use of leukocyte DNA.

Conclusions

The present study suggests that MDR1 2677G>T and 3435C>T polymorphism is not a risk factor for sporadic colon cancer among Bulgarians and that somatic mutation at these sites is not involved in the genesis of colon tumors. Further examination using larger number of samples must be necessary to reach to more reliable conclusions.

Keywords

Bulgarian population Susceptibility Genotype and allele frequencies ABCB1 Single nucleotide polymorphism 

Notes

Acknowledgments

We thank Ekaterina Ilieva for her technical assistance. This study was supported by EUROGENDIS, Maria Curie Fellowship Contract No. QLGA-CT-2000-60005, IPSS-Research Centre for Drug Development, Germany, and Ministry of Education and Science, Bulgaria (Project INP 01.OR.2005), and by the Ministry of Education and Science of Bulgaria, Upgrading of Research Infrastructure Grant No. 05/01.08.2005.

References

  1. Abramson J, Gahlinger P (1999) Computer programs for epidemiologists: PEPI Version 3. Brixton Books, Llanindloes, Powys, WalesGoogle 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 39:361–398PubMedCrossRefGoogle Scholar
  3. Atanasova S, von Ahsen N, Dimitrov T, Armstrong V, Oellerich M, Toncheva D (2004) MDR1 haplotypes modify BEN disease risk: a study in Bulgarian patients with Balkan endemic nephropathy compared to healthy controls. Nephron Exp Nephrol 96:e7–e13PubMedCrossRefGoogle Scholar
  4. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265PubMedCrossRefGoogle Scholar
  5. Benet LZ, Cummins CL, Wu CY (2003) Transporter-enzyme interactions: implications for predicting drug-drug interactions from in vitro data. Curr Drug Metabol 4:393–398CrossRefGoogle Scholar
  6. Brant SR, Panhuysen CI, Nicolae D, Reddy DM, Bonen DK, Karaliukas R, Zhang L, Swanson E, Datta LW, Moran T, Ravenhill G, Duerr RH, Achkar JP, Karban AS, Cho JH (2003) MDR1 Ala893 polymorphism is associated with inflammatory bowel disease. Am J Hum Genet 73:1282–1292PubMedCrossRefGoogle Scholar
  7. Brinkmann U, Eichelbaum M (2001) Polymorphisms in the ABC drug transporter gene MDR1. Pharmacogenomics J 1:59–64PubMedGoogle Scholar
  8. 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 69:169–174PubMedCrossRefGoogle Scholar
  9. Compton CC, Greene FL (2004) The staging of colorectal cancer: 2004 and beyond. CA Cancer J Clin 54:295–308PubMedGoogle Scholar
  10. Cordon-Cardo C, O’Brien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86:695–698PubMedCrossRefGoogle Scholar
  11. Crowley-Weber CL, Dvorakova K, Crowley C, Bernstein H, Bernstein C, Garewal H, Payne CM (2003) Nicotine increases oxidative stress, activates NF-kappaB and GRP78, induces apoptosis and sensitizes cells to genotoxic/xenobiotic stresses by a multiple stress inducer, deoxycholate: relevance to colon carcinogenesis. Chem Biol Interact 145:53–66PubMedCrossRefGoogle Scholar
  12. de la Chapelle A (2004) Genetic predisposition to colorectal cancer. Nat Rev Cancer 4:769–780CrossRefGoogle Scholar
  13. 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 75:17CrossRefGoogle Scholar
  14. Gill S, Sinicrope FA (2005) Colorectal cancer prevention: is an ounce of prevention worth a pound of cure? Semin Oncol 32:24–34PubMedCrossRefGoogle Scholar
  15. Higgins CF (1992) ABC transporters: from microorganisms to man. Annu Rev Cell Biol 8:67–113PubMedCrossRefGoogle Scholar
  16. Hitzl M, Drescher S, van der Kuip H, Schaffeler E, Fischer J, Schwab M, Eichelbaum M, Fromm MF (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 11:293–298PubMedCrossRefGoogle Scholar
  17. Ho GT, Moodie FM, Satsangi J (2003) Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease? Gut 52:759–766PubMedCrossRefGoogle Scholar
  18. Ho GT, Soranzo N, Nimmo ER, Tenesa A, Goldstein DB, Satsangi J (2006) ABCB1/MDR1 gene determines susceptibility and phenotype in ulcerative colitis: discrimination of critical variants using a gene-wide haplotype tagging approach. Hum Mol Genet 15:797–805PubMedCrossRefGoogle Scholar
  19. 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
  20. 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
  21. Johne A, Kopke K, Gerloff T, Mai I, Rietbrock S, Meisel C, Hoffmeyer S, Kerb R, Fromm MF, Brinkmann U, Eichelbaum M, Brockmoller J, Cascorbi I, Roots I (2002) Modulation of steady-state kinetics of digoxin by haplotypes of the P-glycoprotein MDR1 gene. Clin Pharmacol Ther 72:584–594PubMedCrossRefGoogle Scholar
  22. Juliano RL, Ling V (1976) A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 455:152–162PubMedCrossRefGoogle Scholar
  23. 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 25:425–430PubMedCrossRefGoogle Scholar
  24. 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 24:1977–1984PubMedCrossRefGoogle Scholar
  25. 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
  26. Lee CG, Gottesman MM (1998) HIV-1 protease inhibitors and the MDR1 multidrug transporter. J Clin Invest 101:287–288PubMedCrossRefGoogle Scholar
  27. Lilla C, Verla-Tebit E, Risch A, Jager B, Hoffmeister M, Brenner H, Chang-Claude J (2006) Effect of NAT1 and NAT2 genetic polymorphisms on colorectal cancer risk associated with exposure to tobacco smoke and meat consumption. Cancer Epidemiol Biomarkers Prev 15:99–107PubMedCrossRefGoogle Scholar
  28. Lynch HT, de la Chapelle A (2003) Hereditary colorectal cancer. N Engl J Med 348:919–932PubMedCrossRefGoogle Scholar
  29. Mayer U, Wagenaar E, Beijnen JH, Smit JW, Meijer DK, van Asperen J, Borst P, Schinkel AH (1996) Substantial excretion of digoxin via the intestinal mucosa and prevention of long-term digoxin accumulation in the brain by the mdr 1a P-glycoprotein. Br J Pharmacol 119:1038–1044PubMedGoogle Scholar
  30. Millward H, Samowitz W, Wittwer CT, Bernard PS (2002) Homogeneous amplification and mutation scanning of the p53 gene using fluorescent melting curves. Clin Chem 48:1321–1328PubMedGoogle Scholar
  31. 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 24:1219–1224PubMedCrossRefGoogle Scholar
  32. Nicholson FB, Barro JL, Atkin W, Lilford R, Patnick J, Williams CB, Pignone M, Steele R, Kamm MA (2005) Population screening for colorectal cancer. Aliment Pharmacol Ther 22:1069–1077PubMedCrossRefGoogle Scholar
  33. Potocnik U, Glavac MR, Golouh R, Glavac D (2001) The role of P-glycoprotein (MDR1) polymorphisms and mutations in colorectal cancer. Pflugers Arch 442:R182–R183PubMedCrossRefGoogle Scholar
  34. 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 39:340–346PubMedCrossRefGoogle Scholar
  35. Raichev R (1983) Morphological diagnostics of the tumors. Medicine and Physical Culture Press, Sofia [Book in Bulgarian]Google Scholar
  36. Schwab M, Schaeffeler 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 124:26–33PubMedCrossRefGoogle Scholar
  37. Slattery ML, Curtin K, Anderson K, Ma KN, Ballard L, Edwards S, Schaffer D, Potter J, Leppert M, Samowitz WS (2000) Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst 92:1831–1836PubMedCrossRefGoogle Scholar
  38. Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, Borst P, Nooijen WJ, Beijnen JH, van Tellingen O (1997) Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci USA 94:2031–2035PubMedCrossRefGoogle Scholar
  39. 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 297:1137–1143PubMedGoogle Scholar
  40. 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 12:437–450PubMedCrossRefGoogle Scholar
  41. Tanigawara Y (2000) Role of P-glycoprotein in drug disposition. Ther Drug Monit 22:137–140PubMedCrossRefGoogle Scholar
  42. Terwilliger JD, Ott J (1994) Handbook of human genetic linkage. Johns Hopkins University Press, BaltimoreGoogle Scholar
  43. Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987) Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci USA 84:7735–7738PubMedCrossRefGoogle Scholar
  44. 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. Inflamm Bowel Dis 12:33–37PubMedCrossRefGoogle Scholar
  45. von Ahsen N, Oellerich M, Armstrong VW, Schutz E (1999) Application of a thermodynamic nearest-neighbor model to estimate nucleic acid stability and optimize probe design: prediction of melting points of multiple mutations of apolipoprotein B-3500 and factor V with a hybridization probe genotyping assay on the LightCycler. Clin Chem 45:2094–2101Google Scholar
  46. von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW (2001) No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 47:1048–1052Google Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Darinka Todorova Petrova
    • 1
  • Petya Nedeva
    • 2
  • Svilen Maslyankov
    • 3
  • Svetoslav Toshev
    • 4
  • Nikolay Yaramov
    • 4
  • Srebrena Atanasova
    • 5
  • Draga Toncheva
    • 1
    Email author
  • Michael Oellerich
    • 5
  • Nicolas von Ahsen
    • 5
  1. 1.Department of Medical GeneticsMedical University SofiaSofiaBulgaria
  2. 2.Department of PathologySpecialized Oncological HospitalVeliko TarnovoBulgaria
  3. 3.Department of SurgerySpecialized Oncological HospitalVeliko TarnovoBulgaria
  4. 4.Department of SurgeryAleksandrovska University HospitalSofiaBulgaria
  5. 5.Department of Clinical ChemistryGeorg-August-UniversityGöttingenGermany

Personalised recommendations