-

Öz

Aim: Colorectal cancer, the most widely seen type of cancer of the gastrointestinal system, is also the fourth most common cause of death among cancer diseases. Early diagnosis of this type of cancer is important for prognosis and it is reported that the use of inflammatory cytokines in circulation might be useful as a prognostic biomarker. For this purpose, in this study, association of interleukin-6 (IL-6)-174 G/C and interleukin-18 (IL-18) -607 C/A polymorphisms and plasma levels with colorectal cancer was investigated. Method: This study was consist of 96 patients with colorectal cancer and 96 healthy individuals as control group. The polymorphisms of the patients and healthy volunteers groups were investigated by Real-Time PCR. The plasma levels of IL-6 and IL-18 were determined by ELISA method. Results: Upon comparison of the genotype rates of IL-6 G/C (rs1800795) and IL-18 C/A (rs1946518) polymorphisms, a statistically significant difference was found between the patient and the control groups (p<0.001). Plasma levels of IL-6 were significantly higher in the group of patients with colorectal cancer (p<0.001). However, no statistically significant difference was found among the plasma levels of IL-18 in the control group (p<0.966). In order to determine the likelihood of developing CRC due to the combined effects of IL-6 and IL-18 genotypes, the association of genotype combinations of both genes in patients and control group with CRC development was investigated. In such cases that GC- CA and CC-CA genotype combinations exist and both genes are heterozygous, it was determined that there might be a risk of CRC development. Conclusion: Interleukin-6 and interleukin-18 may play a role in the development of colorectal cancer. In addition, the plasma levels of these cytokines can be used for early diagnosis

Anahtar Kelimeler

• IL-6; IL-18; colorectal cancer; plasma level; SNP

İnterlökin-6 ve interlökin-18 gen polimorfizmlerinin ve plazma düzeylerinin kolorektal kanser ile ilişkisi

Öz

Amaç: Gastrointestinal sistemin en sık görülen kanser türlerinden olan kolorektal kanser, kansere bağlı ölüm nedenleri arasında dördüncü sırada bulunmaktadır. Bu kanser türünde erken teşhis, tedavinin prognozu açısından önemlidir ve dolaşımdaki inflamatuvar sitokinlerin prognostik amaçla biyomarker olarak kullanılabileceği bildirilmektedir. Bu amaçla, interlökin-6 (IL-6) -174 G/C ve interlökin-18 (IL-18) -607 C/A polimorfizmleri ve plazma düzeylerinin kolorektal kanser ile ilişkisi araştırıldı. Yöntem: Çalışma kolorektal kanserli 96 hasta ve kontrol grubu 96 sağlıklı bireyden oluşmaktadır. Hasta ve kontrol gruplarının polimorfizmleri Real-Time PZR kullanılarak belirlenmiştir. IL-6 ve IL-18’in plazma düzeyleri ise ELISA yöntemiyle belirlenmiştir. Bulgular: IL-6 G/C (rs1800795) ve IL-18 C/A (rs1946518) polimorfizmlerine ait genotip sıklıkları karşılaştırıldığında kolorektal kanser hastaları ile kontrol grubu arasında anlamlı bir ilişki saptanmıştır (p < 0.001). Plazma düzeyleri açısından ise IL-6 kolorektal kanserli hastalarda anlamlı olarak yüksek bulunmuştur (p < 0.001). Ancak, IL-18 plazma düzeylerinde anlamlı bir fark saptanmamıştır (p < 0.966). IL-6 ve IL-18 genotiplerinin kombine etkisiyle KRK gelişme olasılığını saptamak için, her iki genin hasta ve kontrol gruplarındaki genotip kombinasyonları ile KRK oluşumu arasındaki ilişki kıyaslanmıştır. GC ve CA (p < 0,0001) ile CC ve CA (p < 0.023) genotip kombinasyonlarında her iki genin heterozigot olduğu durumlarda KRK gelişimi açısından risk oluşturabileceği saptanmıştır. Sonuç: İnterlökin-6 ve interlökin-18’in kolorektal kanser gelişiminde rolü olabilir. Ayrıca bu sitokinlerin plazma düzeyleri erken tanı için kullanılabilir.

Anahtar Kelimeler

• IL-6, IL-18, kolorektal kanser, plazma düzeyi, SNP

Kaynakça

1. Büyükdoğan M. Kolorektal Kanserde Genetik ve Etyolojik Faktörler. Selçuk Tıp Derg 2009;25 (3):171-80.
2. Walter V, Jansen L, Hoffmeister M, Brenner H. Smoking and survival of colorectal cancer patients: systematic review and meta-analysis. Annals of Oncology 2014; 25(8):1517-25.
3. Durko L, Malecka-Panas E. Lifestyle Modifications and Colorectal Cancer. Curr Colorectal Cancer Rep 2014;10:45–54.
4. Saygılı G. Kolorektal Karsinomlarda Siklooksijenaz–2 Boyanma
5. Prognostik Parametrelerle Karşılaştırılması. Şişli Etfal Eğitim ve Araştırma Hastanesi. Uzmanlık tezi. İstanbul, 2007. Enziminin Paterni
6. Yaygınlığının 5. Heike K, Rainer P. Serum interleukin-6 level in colorectal cancer patients- a summary of published results. Int. Journal Colorectal Dis 2010; 25(2): 135-40.
7. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso M A. Chronic Inflammation and Cytokines in the Tumor Microenvironment. Journal of Immunology Research 2014;2014:149-85.
8. Bidwell J, Keen L, Gallagher G. Cytokine gene polymorphism in human disease. Genes and Immunity 1999; 1(1): 3-19.

9. Kemik Ö, Kemik A.S, Dülger A.C, Hasırcı İ, Daştan E, Bartın MK, Purisa S, Tüzün S. Karaciğer
10. Hastalarda İnterlökin-6 Düzeyleri. Van Tıp Dergisi 2010;17 (2): 42-5. Kolon
11. Kanserli 9. Lesina M, Wörmann S. M, Neuhöfer P, Song
12. inflammatory and malignant diseases of the pancreas. 2014;26(1): 80–7. Interleukin-6 in Seminars in
13. Immunology 10. Neurath MF, Finotto S. IL-6 signaling in autoimmunity, chronic inflammation and inflammation-associated
14. Growth Factor Rev.2011; 22(2): 83-9.
15. cancer.Cytokine 11. Palma G, Barbieri A, Bimonte S, Zappavigna
16. PA, Ciliberto G, Arra C. Interleukin 18: Friend or foe in cancer. Biochimica et Biophysica Acta 2013;1836(2):296–303.
17. Tangkijvanich P, Thong-ngam D, Mahachai V, Theamboonlers A, Poovorawan Y. Role of serum interleukin-18 as a prognostic hepatocellular
18. Gastroenterol. 2007; 13(32): 4345-9. with World
19. J Kun-Yun Y, Ying-Ying L, Ling-Ling H, Jim-Ray C, Rei-Ping Tang. The −174 G/C Polymorphism in Interleukin-6 (IL-6) Promoter Region is Associated with Serum IL-6 and Carcinoembryonic Antigen Levels in Patients with Colorectal Cancers in Taiwan. J Clain Immunol 2010;30(1): 53-9.
20. Slattery ML, Wolff RK, Herrick JS, Caan BJ, Potter JD. IL6 genotypes and colon and rectal cancer. Cancer Causes Control 2007;18(10): 1095–105.
21. Gangwar R, Mittal B, Mittal RD. Association
22. promoter polymorphism with risk of cervical cancer. Int J Biol Markers 2009; 24(1): 11-58.
23. interleukin-6-174G>C 16.Noqueira de Souza NC, Brenna SM, Campos F, Syrjänen KJ, Baracat EC, Silva ID. Interleukin-6 polymorphisms and the risk of cervical cancer. Int J Gynecol Cancer .2006; 16(3): 1278-82.
24. Vairaktaris E, Yiannopoulos A, Vylliotis A, Yapijakis C, Derka S, Vassiliou S, Nkenke E, Serefoglou Z, Ragos V, Tsigris C, Vorris E, Critselis E, Avgoustidis D,Neukam FW, Patsouris interleukin-6-174
25. polymorphism with increased risk of oral cancer. Int J Biol Markers 2006; 21(4): 246- 50. association of G>C
26. promoter 18. Grivennikov SI, Michael K. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis 2011;(70): 104-8.
27. Samur M, Akbulut H. Kolorektal Karsingenes
28. Hematoloji- Onkoloji 2003;5(3): 115-21. Herediter
29. Durumlar. 20. Lopez PS, Vazquez RCF, Martin J, Sánchez E, Tallada M, Garrido F, Cózar JM, Ruiz-Cabello F. Impact of interleukin-18 polymorphisms-607 and -137 on clinical characteristics of renal cell carcinoma patients. Human Immunology 2010; (71): 309–13. 21. Chatzıtheofylaktou
30. Heterozygosity for Interleukin-18 –607 A/C A,
31. Polymorphism is Associated with Risk for Colorectal Cancer. Antıcancer Research 2007; (27): 3849-54. Yannopoulos A, C. Tsıgrıs
32. Qin AQ, Li RK, Yang CM, Li RK, Yang CM, Huang
33. Association of the IL-18 gene polymorphism with susceptibility to colorectal cancer. Zhonghua Wei Chang Wai Ke Za Zhi. 2012;15(4): 400-3. ZY, Guo
34. HJ. Farjadfar A, Mojtahedı Z, Ghayumı M A, Erfani
35. Interleukin-18 promoter polymorphism is associated with lung cancer: A case-control study. Acta Oncologica 2009;48(7): 971- 6.
36. Wang Q, Zheng L, Yang HL, Bao J. Correlation of serum IL-18 level and IL-18 gene promoter polymorphisms to the risk of cervical cancer. Nan Fang Yi Ke Da Xue Xue Bao. 2008;28(5): 754-7.
37. Merendino RA, Ruello A, Cascinu S, Ferlazzo B, Bene A, Bonanno D, Quattrocchi P, Caristi N, Gangemi S. Influence of 5- fluorouracil and folinic acid on interleukin- 18 production in colorectal cancer patients. Int J Biol Markers 2002;17(1): 63-6.