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Natural immune responses are directly related to tumor immunosurveillance. Preliminary studies of our group suggest that genetic polymorphisms of toll like receptor 9 (TLR9) might be associated with poor prognosis in HCV and alcohol-related cirrhotic patients who underwent liver transplantation for hepatocarcinoma (HCC). The aim of this study was to determine whether TLR9 polymorphisms influence the risk of tumor recurrence after liver transplantation for HCC, regardeless underlying disease.Retrospective study including 163 patients who underwent a first liver transplantation (LT) in our institution between January 1988 and December 2015, and had HCC confirmed in the explanted liver. Microvascular tumoral invasion was assessed in the explanted liver, and after pathological study of liver explant, HCC was re-clasiffied according to Milan criteria.TLR9 -1237C>T and TLR9 -1486C>T were analyzed by real-time PCR and melting curve analysis in all patients.Demographic and clinical data, accordance to Milan criteria, presence of vascular invasion and genotype distributions were compared among patients with or without HCC recurrence with a follow-up of at least 4 years after LT.Tumoral recurrence rate was 14% (n=20) in our series. Median time from LT to HCC recurrence was 35 months. Presence of microvascular tumoral invasion, (OR 15; 95% CI 3.3-68.7; p<0.0001), HCC beyond Milan criteria by multinodularity (OR 6.2; 95% CI 2.5-15.8; p<0.0001), AFP levels >200 mg/dL (OR 9.4; 95% CI 2.6-34.4; p<0.0001), and CC+CT genotype at TLR9 -1486 C/T polymorphism (OR 1.5; 95% CI 1.2-1.9; p=0.03) were significant predictors of post-transplant HCC recurrence. TLR9 -1486C/T polymorphism was not related to other risk factors of HCC recurrence.Toll-like receptor 9 -1486C/T genetic polymorphism might be useful to identify patients at high risk of post-LT HCC recurrence.