Genetic testing for hepatocellular carcinoma: An ambitious goal still to achieve

Background & Aims: A single nucleotide polymorphism 61⁄G (rs4444903) in the epidermal growth factor (EGF) gene has been associated, in two case–control studies, with hepatocellular carcinoma (HCC). We tested associations between demographic, clinical, and genetic data and development of HCC, and developed a simple predictive model in a cohort of patients with chronic hepatitis C and advanced fibrosis. Methods: Black and white subjects from the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial (n = 816) were followed up prospectively for development of a definite or presumed case of HCC for a median time period of 6.1 years. We used the Cox proportional hazards regression model to determine the hazard ratio for risk of HCC and to develop prediction models. Results: Subjects with EGF genotype G/G had a higher adjusted risk for HCC than those with genotype A/A (hazard ratio, 2.10; 95% confidence interval, 1.05–4.23; P = .03). After adjusting for EGF genotype, blacks had no increased risk of HCC risk compared with whites. Higher serum levels of EGF were observed among subjects with at least one G allele (P = .08); the subset of subjects with EGF G/G genotype and above-median serum levels of EGF had the highest risk of HCC. We developed a simple prediction model that included the EGF genotype to identify patients at low, intermediate, and high risk for HCC; 6-year cumulative HCC incidences were 2.3%, 10.4%, and 26%, respectively. Conclusions: We associated the EGF genotype G/G with increased risk for HCC; differences in its frequency among black and white subjects might account for differences in HCC incidence between these Journal of Hepatology 2

Post-liver transplantation graft biopsies should not be used to assess the IL28B donor genotype in HCV recipients.

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Clinical Study Cirrhosis and Rapid Virological Response to Peginterferon Plus Ribavirin Determine Treatment Outcome in HCV-1 IL28B rs12979860 CC Patients

Background. The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. Aim. To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. Methods. Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. Results. 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07-6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics ( = 0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (−) ( = 0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (−) (10/13 (77%) versus 6/17 (35%) = 0.03). Conclusions. In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy

p53-dependent downregulation of metastasis-associated laminin receptor

Based on observations suggesting a role for the tumor suppressor protein p53 in regulating expression of the 67-kDa laminin receptor precursor, 37LRP, we analysed the 37LRP promoter activity in a wild-type p53 (wt p53) ovarian carcinoma cell line and in a cisplatin-resistant subline with mutated p53. We observed an increased promoter activity in wt p53 cells as compared to the mutated-p53 line when the first intron of the 37LRP gene was present in the reporter construct. Cotransfection experiments showed that the promoter is downregulated by both wt and mutated p53. Deletion analysis of the first intron localized an enhancer activity in the first 5' 214 bp that upregulates both 37LRP and SV40 promoter activity and is repressed by both wt and mutant p53. Cotransfection, mutagenesis and gel-shift experiments identified a functional AP-2 cis-acting element in this intron region that is repressed by increased levels of both wt and mutated p53. Coimmunoprecipitation studies revealed AP-2 in physical association in vivo with both wt and mutated p53, indicating for the first time that interaction of p53 with AP-2 is involved in the repression mechanism and in the regulation of genes involved in cancer growth and progression

Cirrhosis and Rapid Virological Response to Peginterferon Plus Ribavirin Determine Treatment Outcome in HCV-1 IL28B rs12979860 CC Patients

Background. The rs12979860 CC genotype of the interleukin 28B (IL28B) polymorphism is associated with high rates of sustained virological response (SVR) to peginterferon (PegIFN) and ribavirin (Rbv) in hepatitis C virus genotype-1 (HCV-1) patients. The impact of baseline predictors of treatment outcome and their interplay with viral kinetics in HCV-1 CC patients has not been fully evaluated. Aim. To identify baseline and on-therapy predictors of treatment failure in HCV-1 IL28B CC patients. Methods. Treatment-naïve HCV-1 patients, compliant to PegIFN and Rbv who did not discontinue treatment for nonvirological reasons, were analyzed. Results. 109 HCV-1 IL28B CC were studied. Sixty were males, 39 with BMI >25, 69 with >600,000 IU/mL HCV RNA, 15 with HCV1a, and 30 with cirrhosis. Overall, 75 (69%) achieved an SVR; cirrhosis was the only baseline predictor of treatment failure (OR: 2.58, 95% CI: 1.07–6.21) as SVR rates were 53% in cirrhotics versus 75% in noncirrhotics (P=0.03). HCV RNA undetectability (<50 IU/mL) at week 4 (RVR) was achieved by 58 patients (53%). The SVR rates were independent of RVR in noncirrhotics, 76% (34/45) RVR (+) and 74% (25/34) RVR (−) (P=0.9). In cirrhotic patients, SVR rates were significantly higher in RVR (+) compared to RVR (−) (10/13 (77%) versus 6/17 (35%) P=0.03). Conclusions. In HCV-1 IL28B CC patients, cirrhosis is the only clinical baseline predictor of PegIFN and Rbv treatment failure. However, in IL28B CC cirrhotics, the achievement of RVR identifies those patients who still have high rates of SVR to Peg-IFN/Rbv therapy

Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B patients

International audienceBACKGROUND & AIMS: Hepatitis B virus (HBV) persistence and the pathobiology of chronic HBV (CHB) infections result from the interplay between viral replication and host immune responses. We aimed to comprehensively analyse the expression of intrahepatic host genes as well as serum and liver HBV markers in a large cohort of untreated CHB patients. METHODS: One-hundred and five CHB patients untreated at the time of liver biopsy (34 HBeAg[+] and 71 HBeAg[-]) were analysed for the intrahepatic expression profile of 67 genes belonging to multiple innate immunity pathways. Results were correlated to serological (quantification of HBsAg [qHBsAg] and HBV DNA) and intrahepatic viral markers (total HBV DNA, pre-genomic RNA and covalently closed circular HBV DNA). RESULTS: Intrahepatic gene expression profiling revealed a strong downregulation of antiviral effectors, interferon stimulated genes, Toll-like and pathogen recognition receptor pathways in CHB patients as compared to non-infected controls, which was not directly correlated to HBV replication. A subset of genes [CXCL10, GBP1, IFITM1, IFNB1, IL10, IL6, ISG15, TLR3, SOCS1, SOCS3] was more repressed in HBeAg(-) respect to HBeAg(+) patients (median of serum HBV DNA 7.9x103vs. 7.9x107IU/ml, respectively). Notably, HBeAg(-) patients with lower qHBsAg (\textless5x103IU/ml) showed a relief of repression of genes belonging to multiple pathways. CONCLUSIONS: Our results show a strong impairment of innate immune responses in the liver of CHB patients. The association of low levels of qHBsAg with gene repression, if confirmed, might prove useful for the identification of patients who would most benefit from immune-modulators and/or HBsAg targeting agents as strategies to restore immune responsiveness. LAY SUMMARY: Chronic hepatitis B virus (HBV) infections represent a major public health problem worldwide. Over 200 million people are chronically infected and at risk of developing chronic hepatitis, liver cirrhosis and cancer. Our work aimed to understand the molecular consequences of chronic hepatitis B in the infected liver. It was conducted in a large cohort of untreated chronically infected HBV patients and analysed the expression of immunity and liver disease-related genes in the liver, with respect to markers of viral replication and persistence. Our results indicate that chronic HBV infection has a suppressive effect on immune responses, which was more pronounced with high levels of hepatitis B virus surface antigen (HBsAg). These data provide novel insight into the mechanisms of HBV persistence in the liver and suggest that approaches aimed at reducing HBsAg levels, may restore immune responsiveness against the viru