CYP2C9 VE VKORC1 GENLERİNİN PROSTAT KANSERİ ETYOLOJİSİNDEKİ ROLLERİNİN ARAŞTIRILMASI

Abstract

1. Amaç: Çalışmamızda, Sitokrom p450 enzimlerini kodlayan CYP ve vitamin K epoksit redüktaz kompleks subünit1 enzimini kodlayan VKORC1 genlerinin alt gruplarındaki tek nükleotit polimorfizmlerinin muhtemel bireysel ve ortak etkilerini prostat kanseri hastalarında araştırmayı amaçladık. Çalışma sonuçları aynı zamanda bu iki gen ile ilgili henüz ortaya konmamış olan bizim populasyonumuza özgü genotip dağılımını da kısmen ortaya koyacaktır.                 

2. Gereç ve Yöntem: Çalışmamıza 48 prostat kanseri tanılı erkek hasta ve 48 sağlıklı erkek birey dâhil edildi. Hasta grubu prostat tanısı almış yaş aralığı 49-86 olan gönüllü bireylerden seçildi. Kontrol grubu prostat kanseri olmadığı belirlenmiş, 51-86 yaş grubundaki gönüllü bireylerden seçildi. Hasta ve kontrol grubu bireylerinin venöz kanları alınarak genomik DNA izolasyonları yapıldı. İzole edilen DNA’ların ilgili gen bölgeleri polimeraz zincir reaksiyonu (PCR) ile çoğaltıldı. Sonrasında PCR ürünleri mikroarray cihazında özel problar yardımıyla çalışıldı. CYP2C9 ve VKORC1 gen bölgelerine ait alt grupların polimorfizmleri tanımlandı ve EpiInfo 3.5.1 istatistik programı ile anlamlılıkları hesaplandı.          

3. Bulgular: Sonuçlarımızda CYP2C9 ve VKORC1 enzimlerini kodlayan genlerin alt gruplarının polimorfizmleri karşılaştırıldığında hasta ve kontrol grubu arasında yüzde olarak önemli farklar görüldü. Örneğin VKORC1 6853 G>C polimorfizmi için kontrol grubunda CC alleli %25 iken hasta grubunda %34,5 olarak tespit edildi. CYP2C9 *3 A>C değişimi için kontrol grubunda CC alleli %79,16 iken hasta grubunda %87,5 olarak tespit edildi.

4. Sonuç: Çalışmamızda sayı ve yüzde olarak hasta ve kontrol grubunda önemli farklar görüldü. CYP2C9 ve VKORC1 geninin alt gruplarının analizleri sonucunda istatistiksel anlamlılık tespit edilmedi. Bunun sebebinin örnek sayısı azlığı ile alakalı olduğu düşünüldü ve ileri çalışmaların konuyu aydınlatacağı düşünüldü.

Keywords

• VKORC1,CYP2C9,Sitokrom p450,Prostat,kanser

The Role of Genes CYP2C9 and VKORC1 in the Ethiology of Prostate Cancer

Abstract

1. Objective: In our study, we aimed to investigate possible individual and common effects of single nucleotide polymorphisms of the gene encoding the enzyme cytochrome p450 (CYP) and the gene encoding the enzyme vitamine K epoxide reductase complex subunit 1 (VKORC1) and their subgroups in patients with prostate cancer. The results of the study also will partially reveal the distribution of genotypes specific to our population, which have not yet been addressed in relation to these two genes.

2. Methods: 48 prostate cancer diagnosed patients and 48 healty male individuals were included in our study. The patient group was selected from volunteers with a prostate-diagnosed age range of 49-86. The control group was selected among without prostate cancer and aged 51-86 years individual. Venous blood was taken from all individuals. Targeted regions were amplified by polymerase chain reaction (PCR) from isolated DNAs. PCR products were genotyped using microarray with appropriate DNA probes. Polymorphisms in the subgroups of the CYP2C9 and VKORC1 gene regions were identified. The results were calculated using the EpiInfo 3.5.1 statistical program.

3. Result: The percentages between patient and control groups showed significant differences when the subgroup polymorphisms of genes encoding CYP2C9 and VKORC1 enzymes were compared. For example, the CC allele of VKORC1 6853 G> C polymorphism found to be %25 in the control and %34.5 in the patient group. The CC allele of CYP2C9 * 3 A> C change found %79.16 in the control and %87.5 in the patient group.

4. Conclusion: Significant differences were seen in number and percentage of patients and control groups in our study. As a result of analysis of the subgroups of CYP2C9 gene and of the VKORC1 gene, statistical significance was not observed. But the percentage results show important differences, though we expect statistical significiance when the numbers of individual is increased

Keywords

• VKORC1,CYP2C9,Cytochrome p450,Prostate

References

1. 1. Parkin DM, Bray FI, Devesa SS. Cancer burden in the year 2000. The global picture. EurJCancer. 2001; 37: 4–66.
2. 2. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics. CA Cancer J Clin 2002; 55: 74-108.
3. 3. Coffey DS. Similarities Of Prostate And Breast Cancer: Evolution, Diet, And Estrogens. Urology. 2001; 57: 31-38.
4. 4. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, et al. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics 1996; 6: 1-42.
5. 5. Rebbeck TR, Jaffe JM, Walker AH, Wein AJ, Malkowicz SB. Modification Of Clinical Presentation Of Prostate Tumors By A Novel Genetic Variant In Cyp3a4. J Natl Cancer Inst. 1998; 90: 1225-1229.
6. 6. Kumagai J, Fujimura T, Takahashi S, Urano T, Ogushi T, Horie-Inoue K et al. Cytochrome P450 2B6 is a growth-inhibitory and prognostic factor for prostate cancer. Prostate. 2007; 1;67: 1029–1037.
7. 7. Yin I, Miyata T. 'Warfarin dose and the of CYP2C9 and VKORC I Jarionnle and perspectives. Thfombosls Research. 2007.
8. 8. Vermeer C, Knapen MHJ, Schurgers LJ. Vitamin K and metabolic bone disease. Clin Pathol. 1998; 51: 424-426.

9. 9. Holzer G, Grasse AV, Zehetmayer S, Bencur P, Bieglmayer C, Mannhalter C. Vitamin K epoxide reductase (VKORC1) gene mutations in osteoporosis: A pilot study. Transl Res. 2010; 156(1): 37-44.
10. 10. Wang Y, Zhen Y, Shi Y, Chen J, Zhang C, Wang X et al. Vitamin K epoxide reductase: a protein involved in angiogenesis. Mol Cancer Res. 2005; 3:317–323.
11. 11. New AS. Bone health: the role of micronutrients. Br Med Bull. 1999; 55(3):619-633.
12. 12. Monographs. Vitamin K2. Altern Med Rev. 2009; 14(3): 284-293.
13. 13. Montes R, Gaona ER, Martinez-Gonzalez MA, Alberca I, Hermid J. The 1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients. British Journal of Haematology. 2006; 133: 183–187.
14. 14. Walsh PC, Retik BA, Vaughan ED, Wein AJ. Campbell’s urology. 9th ed. Philadelphia, Saunders Co. 2007; 3001-3221.
15. 15. Habano W, Gamo T, Sugai T, Otsuka K, Wakabayashi G, Ozawa S. CYP1B1, but not CYP1A1, is downregulated by promoter methylation in colorectalcancers. Int J Oncol. 2009; 34(4): 1085-1091.
16. 16. Liao LH, Zhang H, Lai MP, Lau KW, Lai AK, Zhang JH et al. The association of CYP2C9 gene polymorphisms with colorectal carcinoma in Han Chinese. Clin Chim Acta. 2007; 380(16): 191-196.
17. 17. Levkovich NN, Gorovenko NG, Myasoedov DV. Association of polymorphic G1934A variant (allele *4) of CYP2D6 gene with increased risk of breast cancer development in Ukrainian women. Exp Oncol. 2011; 33(3): 136–139
18. 18. Gan CQ, Wang XY, Cao YD, Ye WX, Liu H, Sun YY. Association of CYP2C19*3 gene polymorphism with breast cancer in Chinese women. Genet Mol Res. 2011; 10(4):3514-3519.
19. 19. Fuster V, Badimon L, Badimon JJ, Chesebro JH. Mechanisms of disease, the pathogenesis of coronary artery disease and the acute coronary syndromes (part one). N Engl J Med. 1992; 326(1): p.242–250
20. 20. Nimptsch K, Rohrmann S, Nieters A, Linseisen J. Serum Undercarboxylated Osteocalcin as Biomarker of Vitamin K Intake and Risk of Prostate Cancer: A Nested Case- Control Study in the Heidelberg Cohort of the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2009; 18(1): 49-56
21. 21. Kellerman G, Shaw CR, Luyten-Kellerman M. Aryl Hydrocarbon Hydroxylase İnducibility And Bronchogenic Carcinoma. N. Engl. J. Med. 1973;298: 934-937.
22. 22. Tamaki Y, Arai T, Sugimura H, Sasaki T, Honda M, Muroi Y, et al. Association between cancer risk and drug-metabolizing enzyme gene (CYP2A6, CYP2A13, CYP4B1, SULT1A1, GSTM1, and GSTT1) polymorphisms in cases of lung cancer in Japan. Drug Metab Pharmacokinet. 2011; 26: 516-522.
23. 23. Ayesh R, Idle JR, Ritchie JC, Crothers MJ, Hetzel MR. Metabolic Oxidation Phenotypes As Markers For Susceptibility To Lung Cancer. Nature, 1984; 312: 169-170.
24. 24. Wang Y, Luo F, Zheng Y, Fan X, Chen J, Zhang Y, Hui R. VKORC1 haplotypes influence the performance characteristics of PIVKAII for screening of hepatocellular carcinoma. Clin Chem Lab Med. 2010; 48: 1475-9.
25. 25. Wijen PA, Bekers O, Drent M. Development of cocaine-induced interstitial lung damage in two CYP2C and VKORC1 variant allele carries. MolDiagn Ther. 2011; 15: 177-80
26. 26. Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med Rev. 2003; 8: 303-318.