TLL1 Variants do not predict hepatocellular carcinoma development in hcv cirrhotic patients treated with direct-acting antivirals

Tolloid like 1 gene (TLL1) variant rs17047200 has been associated with hepatocellular carcinoma (HCC) in Japanese hepatitis C virus (HCV) patients with sustained virological response (SVR) to Interferon or direct-acting antivirals (DAA)-based regimens. We investigated if this holds true also in Caucasian cirrhotic patients cured by DAAs. Consecutive Caucasian HCV cirrhotics receiving DAA between December 2014-2016 in a single Center were enrolled. Cirrhosis was defined histologically (METAVIR F4) or by liver stiffness measurement (LSM >11.9 kPa). TLL1 rs17047200 was analyzed by TaqMan SNP genotyping assay. 452 patients were enrolled: median age 63 (28-87) years, 58% males, 47% HCV-1b, LSM 19.1 (12.0-75.0) kPa, Fibrosis-4 (FIB-4) score 4.9 (0.3-46.0). 96% patients achieved an SVR. TLL1 genotype was AA in 329 (73%), AT/TT in 123 (27%) (MAF=0.14, HWE p>0.05). Patients' clinical features were similar across TLL1 genotypes. After 33 (3-47) months from DAA start, 31 patients developed HCC, 3-year estimated cumulative probability being 7.5% (95% CI 5-10%). Cumulative incidence of HCC was 9% in TLL1 AA vs. 7% in AT/TT patients (p=0.55). Male sex (HR 3.78, 95% CI 1.4-10.1, p=0.008), diabetes (HR 3.5, 95% CI 1.68-7.27, p=0.001) and FIB-4 (HR 1.09, 95% CI 1.03-1.14, p=0.001) were baseline independent predictors of HCC. Incidence of HCC was not influenced by TLL1 genotypes even when considering an additional group of 348 non-cirrhotic patients, being 2% in AA vs. 1% AT/TT patients (p=0.58). In a large cohort of Caucasian HCV cirrhotics treated with DAA, TLL1 variants do not predict HCC development.