TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

BMC Cancer

Hans Dieter Nischalke¹  Ulrich Spengler¹  Jacob Nattermann¹  Tilman Sauerbruch¹  Tobias Müller²  Thomas Berg³  Franziska Wolter¹  Andreas Glässner¹  Marianne Eisenhardt¹  Benjamin Krämer¹  Katarina Riesner¹  Christian Körner¹ 

[1]Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

[2]Medical Clinic for Hepatology and Gastroenterology, Medical University Charité, Augustenburger Platz 1, 13353 Berlin, Germany

[3]Department of Gastroenterology, University Hospital Leipzig, Philipp-Rosenthal-Strasse 27, 04103 Leipzig, Germany

关键词: Cancer;    HCC;    HCV;    A683C (rs20576);    C626G (rs20575);    Polymorphism;    Apoptosis;    DR4;    TRAIL receptor I;   

Others  :  1080522
DOI  :  10.1186/1471-2407-12-85

 received in 2011-08-30, accepted in 2012-03-08,  发布年份 2012

【 摘 要 】

Background

Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (DR4) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed DR4 mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC.

Methods

Frequencies of DR4 gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population.

Results

Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10⁶ IU/ml vs. 1.81 ± 0.23 × 10⁶ IU/ml, p = 0.049).

Conclusions

The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.

【 授权许可】

   
2012 Körner et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Alter MJ: Epidemiology of hepatitis C. Hepatology 1997, 26(3 Suppl 1):62S-65S.
• [2]Moradpour D, Blum HE: Pathogenesis of hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2005, 17(5):477-483.
• [3]Tsukuma H, Hiyama T, Tanaka S, Nakao M, Yabuuchi T, Kitamura T, Nakanishi K, Fujimoto I, Inoue A, Yamazaki H, et al.: Risk factors for hepatocellular carcinoma among patients with chronic liver disease. N Engl J Med 1993, 328(25):1797-1801.
• [4]Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009, 27(9):1485-1491.
• [5]Schutte K, Bornschein J, Malfertheiner P: Hepatocellular carcinoma-epidemiological trends and risk factors. Dig Dis 2009, 27(2):80-92.
• [6]Shepard CW, Finelli L, Alter MJ: Global epidemiology of hepatitis C virus infection. Lancet Infect Dis 2005, 5(9):558-567.
• [7]Mellier G, Huang S, Shenoy K, Pervaiz S: TRAILing death in cancer. Mol Aspects Med 2010, 31(1):93-112.
• [8]Yang A, Wilson NS, Ashkenazi A: Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. Curr Opin Cell Biol 2010, 22(6):837-844.
• [9]Chen B, Liu S, Wang XL, Xu W, Li Y, Zhao WH, Wu JQ: TRAIL-R1 polymorphisms and cancer susceptibility: an evidence-based meta-analysis. Eur J Cancer 2009, 45(14):2598-2605.
• [10]Frank B, Hemminki K, Shanmugam KS, Meindl A, Klaes R, Schmutzler RK, Wappenschmidt B, Untch M, Bugert P, Bartram CR, et al.: Association of death receptor 4 haplotype 626 C-683C with an increased breast cancer risk. Carcinogenesis 2005, 26(11):1975-1977.
• [11]Frank B, Shanmugam KS, Beckmann L, Hemminki K, Brenner H, Hoffmeister M, Chang-Claude J, Burwinkel B: Death receptor 4 variants and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 2006, 15(10):2002-2005.
• [12]Ulybina YM, Kuligina E, Mitiushkina NV, Rozanov ME, Ivantsov AO, Ponomariova DN, Togo AV, Levchenko EV, Shutkin VA, Brenister SI, et al.: Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer. Cancer Lett 2009, 278(2):183-191.
• [13]Wang M, Wang M, Cheng G, Zhang Z, Fu G, Zhang Z: Genetic variants in the death receptor 4 gene contribute to susceptibility to bladder cancer. Mutat Res 2009, 661(1-2):85-92.
• [14]Lan L, Gorke S, Rau SJ, Zeisel MB, Hildt E, Himmelsbach K, Carvajal-Yepes M, Huber R, Wakita T, Schmitt-Graeff A, et al.: Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol 2008, 181(7):4926-4935.
• [15]Ahlenstiel G, Edlich B, Hogdal LJ, Rotman Y, Noureddin M, Feld JJ, Holz LE, Titerence RH, Liang TJ, Rehermann B: Early Changes in Natural Killer Cell Function Indicate Virologic Response to Interferon Therapy for Hepatitis C. Gastroenterology 2011, 141(4):1231-1239.
• [16]Stegmann KA, Bjorkstrom NK, Veber H, Ciesek S, Riese P, Wiegand J, Hadem J, Suneetha PV, Jaroszewicz J, Wang C, et al.: Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection. Gastroenterology 2010, 138(5):1885-1897.
• [17]Kriegl L, Jung A, Engel J, Jackstadt R, Gerbes AL, Gallmeier E, Reiche JA, Hermeking H, Rizzani A, Bruns CJ, et al.: Expression, cellular distribution, and prognostic relevance of TRAIL receptors in hepatocellular carcinoma. Clin Cancer Res 2010, 16(22):5529-5538.
• [18]Chen XP, He SQ, Wang HP, Zhao YZ, Zhang WG: Expression of TNF-related apoptosis-inducing Ligand receptors and antitumor tumor effects of TNF-related apoptosis-inducing Ligand in human hepatocellular carcinoma. World J Gastroenterol 2003, 9(11):2433-2440.
• [19]He S, Chen Y, Chen X, Zhao Y, Wang H, Zhang W, Wang S: Antitumor effects of soluble TRAIL in human hepatocellular carcinoma. J Huazhong Univ Sci Technolog Med Sci 2005, 25(1):51-54.
• [20]Wolf S, Mertens D, Pscherer A, Schroeter P, Winkler D, Grone HJ, Hofele C, Hemminki K, Kumar R, Steineck G, et al.: Ala228 variant of trail receptor 1 affecting the ligand binding site is associated with chronic lymphocytic leukemia, mantle cell lymphoma, prostate cancer, head and neck squamous cell carcinoma and bladder cancer. Int J Cancer 2006, 118(7):1831-1835.
• [21]Zhu H, Dong H, Eksioglu E, Hemming A, Cao M, Crawford JM, Nelson DR, Liu C: Hepatitis C virus triggers apoptosis of a newly developed hepatoma cell line through antiviral defense system. Gastroenterology 2007, 133(5):1649-1659.