Lower Risk Of HCC Research Articles

Exploring the Mediation Effect of Metabolite Levels on the Association Between Gut Microbiota and HCC: A two-step, two-sample bidirectional Mendelian Randomization.

Background: Although the gut microbiota is one of the risk factors for liver cancer, it remains unclear whether the level of metabolites mediates this association. Methods: Utilizing summary data from genome-wide association studies (GWAS), we conducted a two-sample Mendelian Randomization (MR) analysis to explore the causal links between GM, metabolites, and HCC. A two-step MR analysis quantitatively assessed the effect of metabolite-mediated GM on HCC. Results: In our study, we demonstrated that Clostridium leptum was identified as a protective factor against HCC, with no evidence of reverse causality (Inverse-variance weighted [IVW], OR: 0.62 [95% CI, 0.42-0.91]; p = 0.016). Our study also found that the potential connection between the GM and HCC may be mediated by the level of metabolites. An increase of one standard deviation in C. leptum abundance led to a 38% decrease in HCC risk (OR: 0.62 [95% CI, 0.42-0.91]), with a 9% reduction in phosphoethanolamine (PE) levels (OR: 0.91 [95% CI: 0.84-0.99]). PE's mediation proportion was established as -6.725% (95% CI, 12.96% to -26.41%). Conclusion: Our results demonstrate that increasing specific GM abundance can lower HCC risk, mediated by PE levels. We offer new prevention and treatment targets for HCC by adjusting GM.

Improved on-treatment fibrosis-4 during antiviral therapy and lower hepatocellular carcinoma risk in cirrhotic patients with hepatitis B

Normalization of serum alanine aminotransferase (ALT) levels is one of the goals of hepatitis B treatment. However, ALT levels in cirrhosis patients might be normal or mildly elevated regardless of ongoing inflammation. Therefore, we examined whether on-treatment ALT and other potential on-treatment indicators could be clinical surrogates of antiviral therapy in HBV-related cirrhosis. A total of 911 patients with HBV-related liver cirrhosis who started treatment with entecavir or tenofovir were analyzed. At 1 year of antiviral therapy, we evaluated ‘ALT normalization’, ‘undetectable serum HBV DNA’, ‘fibrosis-4 (FIB-4) index improvement’, and ‘serum HBeAg loss’ as potential biomarkers for HCC development. During 6.6 (3.8–10.2) years of follow-up, 222 patients (24.3%) newly developed HCC. Undetectable HBV DNA levels at 1 year were observed in 667 patients (73.2%), and the HCC incidence was significantly lower in this population (adjusted hazard ratio (HR) 0.66, 95% CI 0.50–0.87). Improvement of the FIB-4 index (< 3.25) was associated with a lower risk of HCC in 478 patients with an elevated FIB-4 index (adjusted HR 0.59, 95% CI 0.55–0.82). However, there was no significant difference in HCC risk between those with and without normalization of ALT levels (p = 0.39) among those with elevated ALT levels or between those with and without HBeAg seroconversion (p = 0.55) among HBeAg-positive patients. Therefore, on-treatment FIB-4 levels at 1 year are clinically useful surrogates of antiviral therapy for HBV-related cirrhosis patients.

Effect of diabetes medications and glycemic control on risk of hepatocellular cancer in patients with nonalcoholic fatty liver disease.

In patients with NAFLD, those with type 2 diabetes mellitus (DM) have a high risk of progression to HCC. However, the determinants of HCC risk in these patients remain unclear. We assembled a retrospective cohort of patients with NAFLD and DM diagnosed at 130 facilities in the Veterans Administration between 1/1/2004 and 12/31/2008. We followed patients from the date of NAFLD diagnosis to HCC, death, or 12/31/2018. We used landmark Cox proportional hazards models to determine the effects of anti-DM medications (metformin, insulin, sulfonylureas) and glycemic control (percent of follow-up time with hemoglobin A1c < 7%) on the risk of HCC while adjusting for demographics and other metabolic traits (hypertension, obesity, dyslipidemia). We identified 85,963 patients with NAFLD and DM. In total, 524 patients developed HCC during a mean of 10.3 years of follow-up. Most common treatments were metformin monotherapy (19.7%), metformin-sulfonylureas (19.6%), insulin (9.3%), and sulfonylureas monotherapy (13.6%). Compared with no medication, metformin was associated with 20% lower risk of HCC (HR, 0.80; 95% CI, 0.93-0.98). Insulin had no effect on HCC risk (HR, 1.02; 95% CI, 0.85-1.22; p = 0.85). Insulin in combination with other oral medications was associated with a 1.6 to 1.7-fold higher risk of HCC. Adequate glycemic control was associated with a 31% lower risk of HCC (HR, 0.69; 95% CI, 0.62-0.78). In this large cohort of patients with NAFLD and DM, use of metformin was associated with a reduced risk of HCC, whereas use of combination therapy was associated with increased risk. Glycemic control can serve as a biomarker for HCC risk stratification in patients with NAFLD and diabetes.

Genetic polymorphism of fibroblast growth factor receptor 2 and trinucleotide repeat-containing 9 influence the susceptibility to HCV-induced hepatocellular carcinoma

BackgroundFibroblast growth factor receptor 2 (FGFR2) and trinucleotide repeat-containing 9 (TNRC9) gene polymorphisms have been associated with some cancers. We aimed to assess the association of FGFR2 rs2981582 and TNRC9 rs12443621 polymorphisms with hepatocellular cancer risk. MethodsOne hundred patients with HCV-induced HCC, 100 patients with chronic HCV infection, and 100 controls were genotyped for FGFR2 rs2981582 and TNRC9 rs12443621 using allele-specific Real-Time PCR analysis. ResultsFGFR2 rs2981582 genotype TT was associated with increased risk of HCC when compared to controls (OR = 3.09, 95% CI = 1.24–7.68). However, it was significantly associated with a lower risk of HCC when using HCV patients as controls (OR = 0.21, 95% CI = 0.09–0.5), and T-allele of FGFR2 appears to be a protective allele against HCC in HCV patients (OR = 0.42, 95% CI = 0.21−0.85). While AG and GG genotypes of TNRC9 rs12443621 were linked with significantly increased risk of HCC (OR = 3.91, 95% CI = 2.02–7.6 and OR = 9.26, 95% CI = 3.21–26.7 respectively) and HCV patients carrying G allele were at increased risk of HCC by 2.7-fold. A significant high frequency of small tumor size and early-stage of HCC were observed in patients carrying FGFR2 rs2981582 genotype CT and TT (P = 0.029 and <0.001 respectively), while, TNRC9 rs12443621 genotype AG and GG were associated large tumor size and late-stage of HCC (P < 0.001 and 0.015 respectively). ConclusionsSNPs in rs2981582 for FGFR2 and rs12443621 for TNRC9 gene were associated with HCC susceptibility, suggesting their implication in hepatocarcinogenesis in chronically HCV-infected patients.

Clinical and Molecular-Based Approach in the Evaluation of Hepatocellular Carcinoma Recurrence after Radical Liver Resection.

Simple SummaryHepatocellular carcinoma (HCC) recurrence is still a major issue after liver resection. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex process of accumulation of somatic genomic alterations, which has not been completely understood, especially with respect to tumor recurrence. The aim of this study is to complement potentially predictive clinical factors with next-generation sequencing genomic profiling and loss of heterozygosity analysis. We confirmed that serum bilirubin level, number of HCC nodules and size of the larger nodule are linked to a higher risk of tumor recurrence. Loss of heterozygosity in the PTEN loci was found to be associated with a lower risk of HCC recurrence.Background: Hepatic resection remains the treatment of choice for patients with early-stage HCC with preserved liver function. Unfortunately, however, the majority of patients develop tumor recurrence. While several clinical factors were found to be associated with tumor recurrence, HCC pathogenesis is a complex process of accumulation of somatic genomic alterations, which leads to a huge molecular heterogeneity that has not been completely understood. The aim of this study is to complement potentially predictive clinical and pathological factors with next-generation sequencing genomic profiling and loss of heterozygosity analysis. Methods: 124 HCC patients, who underwent a primary hepatic resection from January 2016 to December 2019, were recruited for this study. Next-generation sequencing (NGS) analysis and allelic imbalance assessment in a case-control subgroup analysis were performed. A time-to-recurrence analysis was performed as well by means of Kaplan–Meier estimators. Results: Cumulative number of HCC recurrences were 26 (21%) and 32 (26%), respectively, one and two years after surgery. Kaplan–Meier estimates for the probability of recurrence amounted to 37% (95% C.I.: 24–47) and to 51% (95% C.I.: 35–62), after one and two years, respectively. Multivariable analysis identified as independent predictors of HCC recurrence: hepatitis C virus (HCV) infection (HR: 1.96, 95%C.I.: 0.91–4.24, p = 0.085), serum bilirubin levels (HR: 5.32, 95%C.I.: 2.07–13.69, p = 0.001), number of nodules (HR: 1.63, 95%C.I.: 1.12–2.38, p = 0.011) and size of the larger nodule (HR: 1.11, 95%C.I.: 1.03–1.18, p = 0.004). Time-to-recurrence analysis showed that loss of heterozygosity in the PTEN loci (involved in the PI3K/AKT/mTOR signaling pathway) was significantly associated with a lower risk of HCC recurrence (HR: 0.35, 95%C.I.: 0.13–0.93, p = 0.036). Conclusions: multiple alterations of cancer genes are associated with HCC progression. In particular, the evidence of a specific AI mutation presented in 20 patients seemed to have a protective effect on the risk of HCC recurrence.

Abstract 4647: Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study

Abstract Background. There is a limited research on the association between combined dietary measures and liver cancer risk. We investigated the association between the four diet-quality index (DQI) scores, the Alternative Health Eating Index-2010 (AHEI-2010), Alternate Mediterranean Diet (aMED); Dietary Approaches to Stop Hypertension (DASH) and Heathy Diet Indicator (HDI) with liver cancer risk, using data from the Singapore Chinese Health Study, a prospective cohort of 63,257 Chinese men and women aged 45-74 at enrollment in 1993-1998 with up to 25 years of follow-up. Methods. The Cox proportional hazard regression method was used to estimate hazard ratio (HR) and its 95% confidence interval (CI) of HCC with each DQI after adjustment for multiple potential confounders. The unconditional logistic regression method was used to evaluate the associations between the DQIs and HCC risk among a subset of individuals who tested negative for hepatitis B surface antigen (HBsAg). Results. During an average 17.7 years of follow-up, 561 incident HCC cases were identified. High scores of AHEI-2010, aMED and DASH, representing higher dietary quality, were associated with lower risk of HCC (all Ptrend&amp;lt;0.05). Compared with the lowest quartile, HRs (95% CIs) of HCC risk for the highest quartile of AHEI-2010, aMED and DASH were 0.71 (0.55-0.91), 0.73 (0.54-0.98), and 0.68 (0.52-0.89), respectively. These inverse associations were stronger in men than in women. No significant association between HDI and HCC risk was observed. Among HBsAg-negative individuals, similar inverse associations were observed, and the strongest inverse association was for aMED that reached statistically significance level (HRQ4vsQ1=0.48, 95% CI: 0.24-0.98). Conclusion. Higher scores of AHED, aMED, and DASH were significantly associated with reduced risk of HCC in this Asian population. The findings support the notion that adherence to a healthier diet may lower the risk of HCC, suggesting that dietary modification may be an effective approach for primary prevention of HCC. Funding: The Singapore Chinese Health Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01 CA144034 and UM1 CA182876). Citation Format: Hung N. Luu, Nithya Neelakantan, Ting-ting Geng, Renwei Wang, Jennifer Adams-Haduch, Aizhen Jin, Rob M. Van Dam, Woon-Puay Koh, Jian-Min Yuan. Diet quality indexes and risk of hepatocellular carcinoma: Findings from the Singapore Chinese Health Study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4647.

Risk factors for liver Cancer in HIV endemic areas of Western Kenya

BackgroundHepatocellular carcinoma (HCC) is a malignant cancer of the liver and a leading cause of cancer-related mortality worldwide. Human immunodeficiency virus (HIV) has not been known to have a direct causal relationship with HCC despite independently causing inflammation of the liver. However, little is known on risk factors for HCC patients in an HIV endemic area. The objective of this study was to ascertain the risk factors of HCC and its association with HIV infection.MethodsThis was an un-matched case-control study conducted between June 2015 and June 2016 in Kisumu County Referral Hospital, Kenya. The study enrolled 257 patients with HCC cases and 257 controls. A multivariable logistic regression analysis was used to assess the risk factors for HIV and controlling for exploratory variables. Independent t-test was used to compare means. Exposure variable with values < 0.05 were considered to be statistically significant.ResultsHCC cases were more likely to be above 35 years old compared to controls (88.3% vs 23.0%), [aOR =51.6, 95% CI (27.8–95.6), P < 0.001)]. HBV infected patients have higher risk of HCC (47.1% vs 30.4%), [aOR = 3.3; 95% CI (1.7–5.0), P < 0.0001)]. HIV positive patients were more likely to have HCC than HIV negative patients (33.5% vs 10.9%), [aOR =4.3, 95% CI (2.2–8.4)), P < 0.001]. Females have lower risk of HCC than males (32.7 vs 23.7) [aOR = 0.2, 95% CI (0.1–0.4), P < 0.001]. The majority of HCC patients were at the time of diagnosis at stages C (35.1%) and D (48.6%) according to the Barcelona Clinic Liver Clinic (BCLC) criteria.ConclusionLiver cancer was more frequent among adults and subjects co-infected with HBV and HIV. Thus, HIV represents an additional risk factor for liver cancer in this Kenyan population. Regular health screening of HIV and HBV infected subjects may significantly improve the early diagnosis and effective therapy of liver cancer.

Territory-wide population-based study of chronic hepatitis C infection and implications for hepatitis elimination in Hong Kong.

To study the epidemiology of chronic hepatitis C virus infection in Hong Kong and to estimate the service gap for achieving the WHO hepatitis elimination targets of attaining a diagnosis rate of 90%, treatment rate of 80% and 65% reduction in mortality rate by 2030. From January 2005 to March 2017, patients who were tested positive for anti-HCV were retrospectively retrieved from all public hospitals in Hong Kong. The epidemiological data of 15 participating hospitals were analysed. A total of 11309 anti-HCV+ patients were identified and the estimated diagnosis rate was 50.9%. Our HCV-infected patients were ageing (median age 59). The all-cause mortality rate increased from 26.2 to 54.8 per 1000 person-years over the last decade. Our estimated treatment rate was 12.4%. Among the treated patients, 93.6% had received pegylated interferon/ribavirin (Peg-IFN/RBV) but only 10.8% had received interferon-free direct-acting antivirals (DAAs). In a cohort of 1533 patients, 39% already had advanced liver fibrosis or cirrhosis. The sustained virological response rate for Peg-IFN/RBV and DAAs were 74.8% and 97.2% respectively. However, more than 70% of patients were not subjected to interferon treatment for various reasons. Patients who achieved SVR were associated with a significantly lower risk of HCC (4.7% vs 9.6%, P=0.005) and death (1.7% vs 23.8%, P<0.001). Our diagnosis rate, treatment rate and mortality rate reduction were still low, particularly the Peg-IFN outcomes, making it difficult to meet the WHO hepatitis elimination targets. A more generalized use of DAAs is urgently needed to improve the situation.

Ambient ultraviolet radiation exposure and hepatocellular carcinoma incidence in the United States

BackgroundHepatocellular carcinoma (HCC), the most commonly occurring type of primary liver cancer, has been increasing in incidence worldwide. Vitamin D, acquired from sunlight exposure, diet, and dietary supplements, has been hypothesized to impact hepatocarcinogenesis. However, previous epidemiologic studies examining the associations between dietary and serum vitamin D reported mixed results. The purpose of this study was to examine the association between ambient ultraviolet (UV) radiation exposure and HCC risk in the U.S.MethodsThe Surveillance, Epidemiology, and End Results (SEER) database provided information on HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries across the U.S. Ambient UV exposure was estimated by linking the SEER county with a spatiotemporal UV exposure model using a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) for the association between ambient UV exposure per interquartile range (IQR) increase (32.4 mW/m2) and HCC risk adjusting for age at diagnosis, sex, race, year of diagnosis, SEER registry, and county-level information on prevalence of health conditions, lifestyle, socioeconomic, and environmental factors.ResultsHigher levels of ambient UV exposure were associated with statistically significant lower HCC risk (n = 56,245 cases; adjusted IRR per IQR increase: 0.83, 95% CI 0.77, 0.90; p < 0.01). A statistically significant inverse association between ambient UV and HCC risk was observed among males (p for interaction = 0.01) and whites (p for interaction = 0.01).ConclusionsHigher ambient UV exposure was associated with a decreased risk of HCC in the U.S. UV exposure may be a potential modifiable risk factor for HCC that should be explored in future research.

Prediagnostic selenium status and hepatobiliary cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort

Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract. We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression. HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63). These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development.

Rapid, Sensitive, and Accurate Evaluation of Drug Resistant Mutant (NS5A-Y93H) Strain Frequency in Genotype 1b HCV by Invader Assay.

Daclatasvir and asunaprevir dual oral therapy is expected to achieve high sustained virological response (SVR) rates in patients with HCV genotype 1b infection. However, presence of the NS5A-Y93H substitution at baseline has been shown to be an independent predictor of treatment failure for this regimen. By using the Invader assay, we developed a system to rapidly and accurately detect the presence of mutant strains and evaluate the proportion of patients harboring a pre-treatment Y93H mutation. This assay system, consisting of nested PCR followed by Invader reaction with well-designed primers and probes, attained a high overall assay success rate of 98.9% among a total of 702 Japanese HCV genotype 1b patients. Even in serum samples with low HCV titers, more than half of the samples could be successfully assayed. Our assay system showed a better lower detection limit of Y93H proportion than using direct sequencing, and Y93H frequencies obtained by this method correlated well with those of deep-sequencing analysis (r = 0.85, P <0.001). The proportion of the patients with the mutant strain estimated by this assay was 23.6% (164/694). Interestingly, patients with the Y93H mutant strain showed significantly lower ALT levels (p=8.8 x 10-4), higher serum HCV RNA levels (p=4.3 x 10-7), and lower HCC risk (p=6.9 x 10-3) than those with the wild type strain. Because the method is both sensitive and rapid, the NS5A-Y93H mutant strain detection system established in this study may provide important pre-treatment information valuable not only for treatment decisions but also for prediction of disease progression in HCV genotype 1b patients.

P0369 : Circulating SCCA-IgM complex is a useful biomarker to predict the outcome of therapy in HCC patients

s / Digestive and Liver Disease 46S (2014) e136–e141 e137 all 248 patients had reached HBV undetectability <20UI/ml within one year of therapy. Thirty of these patients developed HCC during follow-up. These patients had the GG in 26.7% and the GA or AA 73.3%. Among the 218 who did not develop HCC, 46.3% were GG and 53.7% GA/AA (OR: 2.37; 95% CI: 1.01–5.56 p 0.041). Patients on NUCswith CH had a lower risk of HCC than thosewith LC (OR: 0.13; 95% CI: 0.04–0.40; p=0.0001) and cirrhotic patients with GG had a lower risk of HCC than patients with AG/AA (OR: 0.35; 95% CI: 0.13–0.96; p=0.036). Conclusions: The AG or AA genotypes of rs4374383 SNP of the MERTK gene confers a significant additional risk of developing HCC to patientswith chronicHBV infection, especially in the presence of cirrhosis. Testing patients on NUCs suppressive treatment for this SNP may allow to tailor surveillance for HCC. http://dx.doi.org/10.1016/j.dld.2014.08.019

P0771 : C-SCAPE: Efficacy and safety of 12 weeks of grazoprevir +/- elbasvir +/- ribavirin in patients with HCV GT2, 4, 5 or 6 infection

death (aHR=1.51, 95%CI 1.23–1.85). HCC screening was lower in the treated than the untreated group (0.20 vs. 0.28 screenings/personyear). Nevertheless, patients with SVR had a lower risk of HCC (aHR=0.54, 95%CI 0.34–0.84) compared to treated patients without SVR, while treated patients without SVR had a higher risk of HCC than untreated patients (aHR=1.97, 95%CI 1.48–2.63). Blacks had a higher risk of non-liver cancer compared to whites (aHR=2.09, 95%CI 1.44–3.02), while treatment, with or without SVR, had no effect. Older age was a risk factor for all outcomes. Conclusions: In a large, real world US multicenter cohort following both treated and untreated HCV patients, presence of moderateto-advanced fibrosis and genotype 3 independently increased risk of HCC, while SVR reduced development of HCC by 46%. Treatment, regardless of whether SVR was attained, reduced allcause mortality.

Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans

The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking. The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset. Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer. Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.