MDR1 C3435T POLİMORFİZMİ: KOLOREKTAL KANSER RİSKİ İLE İLİŞKİSİ ÜZERİNE BİR ÖN ÇALIŞMA

Year 2021, , 531 - 536, 01.10.2021

Gülçin Özkara , İlhan Yaylım Soykan Arıkan Turgay İşbir Hülya Yılmaz Aydoğan

https://doi.org/10.26650/IUITFD.2021.849990

Abstract

Amaç: Bir veya çoklu genetik mekanizmaların kombinasyonuyla oluşan heterojen bir hastalık olan kolorektal kanser (KRK) dünyada en sık görülen üçüncü kanserdir. P-glikoproteini (P-gp) kodlayan çoklu ilaç direnci geni-1 (Multiple drug resistance-1 (MDR1)) ilaçların biyoyararlanımı ve hücre toksisitesinde rol oynar. Bu çalışmada, Türk popülasyonunda MDR1 geni C3435T polimorfizmi ve KRK riski arasındaki olası ilişkiyi araştırmayı amaçladık. Gereç ve Yöntemler: Çalışmamıza KRK hastası (26 erkek, 17 kadın) 43 kişi ve 48 sağlıklı kontrol (34 erkek, 14 kadın) dahil edilmiştir. MDR1 C3435T genotipleri Restriksiyon Fragman Uzunluk Polimorfizmi RFUP) yöntemiyle belirlenmiştir. Bulgular: MDR1 C3435T genotiplerinin dağılımı açısından çalışma grupları arasında istatistiksel anlamlılık elde edilmiştir. KRK hasta grubunda MDR1 C3435T CC, TT ve CT genotiplerinin sıklığı sırasıyla %16,3, %32,6 ve %51,2 olarak bulunmuştur. Homozigot TT genotipi frekansı KRK hastalarında %32,6 bulunurken kontrollerde %14,6 (p=0,04; OR=2,82, 95% CI: 1,01-7,87) olarak tespit edilmiştir. Hastalar ve sağlıklı kontroller karşılaştırıldığında MDR1 C3435T polimorfizmi TT genotipi taşıyıcıları KRK gelişimi için 2,8 kat (p<0,05) artmış risk altında bulunmuştur. Sonuç: Sonuçlarımız MDR1 C3435T polimorfizminin Türk popülasyonunda KRK gelişimi için genetik risk faktörlerinden biri olabileceğini göstermektedir.

Keywords

MDR1, C3435T, polimorfizm, kolorektal kanser, Türk popülasyonu

MDR1 C3435T POLYMORPHISM: A PRELIMINARY STUDY ON ITS RELATIONSHIP WITH THE RISK OF COLORECTAL CANCER

Abstract

Objective: Colorectal carcinoma (CRC) is the third most frequent cancer in the world and a heterogenious disease which aroze from one or a combination of different genetic mechanisms. The multiple drug resistance-1 (MDR1) gene which encodes P-glycoprotein (P-gp) plays a part in the bioavailability of drugs and cell toxicity. In the current study, we aimed to investigate the possible relation between the MDR1 gene C3435T polymorphism and CRC risk in the Turkish population. Material and Methods: Forty three patients (26 men, 17 women) with CRC and 48 healthy controls (34 men, 14 women) were included in the study. The MDR1 C3435T genotypes were determined by the Restriction Fragment Length Polymorphism (RFLP) method. Results: Statistical significance was obtained in terms of genotype distributions of MDR1 C3435T genotypes between study groups. The frequencies of MDR1 C3435T CC, TT and CT genotypes in the CRC patient group were found as 16.3%, 32.6% and 51.2%, respectively. The frequency of the homozygous TT genotype was found as 32.6% in CRC patients while it was identified as 14.6% in controls (p=0.04; OR=2.82, 95% CI: 1.01-7.87). When the patients were compared with the healthy population, TT genotype carriers of MDR1 C3435T polymorphism were found at 2.8-fold (p<0.05 ) increased risk for the development of CRC. Conclusion: Our results show that the MDR1 C3435T polymorphism might be one of the genetic risk factors for CRC development in the Turkish population.

Keywords

MDR1, C3435T, polymorphism, colorectal cancer, Turkish population

References

• 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians. 2018 Nov; 68(6): 394-424.
• 2. Bogaert J, Prenen H. Molecular genetics of colorectal cancer. Ann Gastroenterol. 2014 27(1): 9-14.
• 3. Tariq K, Ghias K. Colorectal cancer carcinogenesis: a review of mechanisms. Cancer Biol. Med. 2016 Mar; 13(1): 120-135.
• 4. Nooter K, Stoter G. Molecular mechanisms of multidrug resistance in cancer chemotherapy. Pathol Res Pract. 1996 Jul; 192(7): 768-780.
• 5. Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4; 258(5088): 1650-1654.
• 6. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat Rev Cancer. 2002 Jan; 2(1): 48-58.
• 7. Jordan A, Scholz R. Selection and characterization of heat-resistant variants of multidrug-resistant human gastric carcinoma cell lines. Exp. Oncol. 2005 Mar; 27 (1): 18-23.
• 8. Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM. P-glycoprotein: from genomics to mechanism. Oncogene. 2003 Oct 20; 22(47): 7468-7485.
• 9. Schinkel AH. The physiological function of drug-transporting P-glycoproteins. Semin Cancer Biol. 1997 Jun; 8 (3): 161–170.
• 10. Lockhart AC, Tirona RG, Kim RB. Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther. 2003 Jul; 2(7): 685-698.
• 11. Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, Johne A. 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. 2000 Mar 28; 97(7): 3473–3478.
• 12. Kurzawski M, Drozdzik M, Suchy J, Kurzawski G, Bialecka M, Gornik W, et al. Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol. 2005 Jul; 61(5-6): 389-394.
• 13. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T, et al. 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. 2002 Aug; 71(4): 297-303.
• 14. Turgut S, Yaren A, Kursunluoglu R, Turgut G. MDR1 C3435T polymorphism in patients with breast cancer. Arch Med Res. 2007 ; 38: 539-544.
• 15. Taheri M, Mahjoubi F, Omranipour R. Effect of MDR1 polymorphism on multidrug resistance expression in breast cancer patients. Genet Mol Res. 2010 Jan; 12:9 (1): 34-40.
• 16. Siegsmund M, Brinkmann U, Scháffeler E, Weirich G, Schwab M, Eichelbaum M, et al. Association of the P-glycoprotein transporter MDR1 (C3435T) polymorphism with the susceptibility to renal epithelial tumors. J Am Soc Nephrol. 2002 Jul; 13(7): 1847-1854.
• 17. Baldissera VD, de Mattos AA, Corral GP, de Araujo FB, Marroni CA, de Mello Brandao AB, et al. Evaluation of the C3435T polymorphisim in the MDR1 gene in patients with hepatocellular carsinoma. Ann Hepatol. 2012 Nov-Dec; 11(6): 899-906.
• 18. Ozawa S, Soyama A, Saeki M, Fukushima-Uesaka H, Itoda M, Koyano S, et al. Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1.Drug Metab Pharmacokinet. 2004 Apr; 19(2): 83-95.
• 19. Cascorbi I, Gerloff Th, Johne A, Meisel CH, Hoffmeyer S, Schwab M. Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects. Clin Pharmacol Ther. 2001 Mar; 69(3): 169–174.
• 20. Tan EK, Drozdzik M, Bialecka M, Honczarenko K, Klodowska-Duda G, Teo YY, et al. Analysis of MDR1 haplotypes in Parkinson's disease in a white population. Neurosci Lett. 2004 Dec 6; 372(3): 240-244.
• 21. Miller SA, Dykes DD, Polesky HS. Simples salting out procedure for extracting DNA from human nucleated cells. Nucleic Acid Res. 1988 Feb 11; 16(3): 1215.
• 22. Sills GJ, Mohanraj R, Butler E, McCrindle S, Collier L, Wilson EA, et al. Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment. Epilepsia. 2005 Apr; 46(5): 643-647.
• 23. Ho GT, Moodie FM, Satsangi J. Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease. Gut. 2003 May; 52(5): 759–766. 24. Tanigawara Y. Role of P-glycoprotein in drug disposition. Ther Drug Monit. 2000 Feb; 22(1): 137–140.
• 25. Jamroziak K, Młynarski W, Balcerczak E, Mistygacz M, Trelinska J, Mirowski M, et al. Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol. 2004 May; 72(5): 314-321.
• 26. Illmer T, Schuler US, Thiede C, Schwarz UI, Kim RB, Gotthard S, et al. MDR1 gene polymorphisms affect therapy outcome in acute myeloid leukemia patients. Cancer Res. 2002 Sep 1; 62(17): 4955-4962.
• 27. Drescher S, Schaeffeler E, Hitzl M, Hofmann U, Schwab M, Brinkmann U, et al. MDR1 gene polymorphisms and disposition of the P-glycoprotein substrate fexofenadine. Br J Clin Pharmacol. 2002 May; 53(5): 526-534.
• 28. Eichelbaum M, Fromm MF, Schwab M. Clinical aspects of the MDR1 (ABCB1) gene polymorphism. Ther Drug Monit. 2004 Apr; 26(2):180-185.
• 29. Jeleń AM, Sałagacka A, Żebrowska MK, Mirowski M, Talarowska M, Gałecki P, et al. The Influence of C3435T Polymorphism of the ABCB1 Gene on Genetic Susceptibility to Depression and Treatment Response in Polish Population - Preliminary Report. Int J Med Sci. 2015 Nov 20; 12(12): 974-979.
• 30. Humeny A, Rodel F, Rodel C, Sauer R, Fuzesi L, Becker C. MDR1 single nucleotide polymorphism C3435T in normal colorectal tissue and colorectal carcinomas detected by MALDI-TOF mass spectrometry. Anticancer Res. 2003 May-Jun; 23 (3B): 2735–2740.
• 31. Jin SS, Song WJ. Association between MDR1 C3435T polymorphism and colorectal cancer risk: A meta-analysis. Medicine (Baltimore). 2017 Dec; 96(51): e9428.
• 32. Özhan G, Kara M, Sari FM, Yanar HT, Ercan G, Alpertunga B. Associations between the functional polymorphisms in the ABCB1 transporter gene and colorectal cancer risk: a case-control study in Turkish population. Toxicology Mechanisms and Methods. 2013 May; 23(4): 235-239.