Hepatitis C-associated Hepatocellular Carcinoma Research Articles

Extracellular Vesicles Contribute to Viral-Induced Hepatocellular Carcinoma: Understanding Their Involvement in Viral Hepatitis and Their Potential as Biomarkers for Early Hepatocellular Carcinoma Detection.

The high global prevalence of hepatitis B and hepatitis C and the poor prognosis of hepatitis B and hepatitis C-associated hepatocellular carcinoma (HCC), necessitates the early diagnosis and treatment of the disease. Recent studies show that cell-to-cell communication via extracellular vesicles (EVs) is involved in the HCC progression. The objective of the following study was to explore the role of EVs in the progression of viral-induced HCC and investigate their potential for the early diagnosis of cancer. First, the mRNA derived from EVs of HCC patients was compared to the mRNA derived from EVs from the healthy controls. Expression analysis of ANGPTL3, SH3BGRL3, and IFITM3 genes from the EVs was done. Afterward, to confirm whether hepatocytes can uptake EVs, HuH7 cells were exposed to EVs, and the expression analysis of downstream target genes (AKT, TNF-α, and MMP-9) in Huh7 cells was done. Transcriptional analysis showed that in the EVs from HCC patients, the expression levels of ANGPTL3, SH3BGRL3, and IFITM3 were significantly increased by 2.62-, 4.3-, and 9.03-folds, respectively. The downstream targets, AKT, TNF-α, and MMP-9, also showed a considerable change of 4.1-, 1.46-, and 5.05-folds, respectively, in Huh7 cells exposed to HCC EVs. In conclusion, the following study corroborates the role of EVs in HCC progression. Furthermore, the significant alteration in mRNA levels of the selected genes demonstrates their potential to be used as possible biomarkers for the early diagnosis of HCC.

Utility of a microRNA panel in diagnosis and prognosis of hepatitis C-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and the leading cause of cancer mortality. Various studies have linked dysregulated microRNA expression to liver cancers, but those related to viral hepatitis-related HCC are limited. We investigated the diagnostic and prognostic roles of circulating miR-331-3p, miR-23b-3p, and miR-3194-5p in EDTA-treated blood samples of 50 hepatitis C virus (HCV) HCC patients, 50 HCV cirrhotic patients, and 50 healthy controls using quantitative real-time polymerase chain reaction. We found that miR-23b-3p and miR-3194-5p were significantly downregulated, whereas miR-331-3p was upregulated in HCC patients compared with controls. Also, these miRNAs were significantly dysregulated in HCC compared with cirrhotic patients. For the diagnosis of HCC, miR-331-3p and the combined miRNAs panel had the highest area under the curve (AUC), followed by miR-3194-5p. The highest AUC for differentiating metastatic from nonmetastatic patients was shown by miR-331-3p and the combined miRNAs panel, followed by miR-23b-3p. Dysregulation of miRNAs was associated with poor clinicopathological manifestations. Finally, miR-331-3P was found to be an independent risk factor for metastatic lesions in HCC. Overall, the assessed miR-331-3p, miR-23b-3p, and miR-3194-5p were significantly associated with poor clinicopathological features of HCC and could be used to discriminate HCV-related HCC patients from cirrhosis and differentiating metastatic from nonmetastatic patients, primarily miR-331-3p along with combined miRNAs. Moreover, miR-331-3p was found to be an independent factor for metastatic lesions.

Treatment Disparities among Mental Health Patients with Hepatitis C-Associated Hepatocellular Carcinoma: An US Safety Net Collaborative (USSNC) Analysis

Introduction: Hepatocellular carcinoma (HCC) is most commonly caused by hepatitis C(HCV)-induced cirrhosis in the United States. Among patients with HCV-associated HCC, HCV treatment is associated with improved survival. Patients with mental health disorders face disparate access to HCV treatment. We sought to evaluate whether mental health impacted HCV treatment at academic and safety net hospitals (SNH) using the US Safety Net Collaborative (USSNC) database.

What Is the Optimal Bridging Therapy for Patients with Hepatitis C-associated Hepatocellular Carcinoma Awaiting Liver Transplant? An Analysis of the United States HCC Liver Transplantation Consortium

Introduction: Patients with hepatitis C (HCV)-associated hepatocellular carcinoma (HCC) often receive bridging therapy in the form of liver-directed therapy (LDT) while awaiting liver transplant (LT). The optimal modality of LDT, with respect to both cancer outcomes and response to direct-acting antiviral (DAA) therapy, remains unknown. Methods: The United States HCC Liver Transplantation Consortium was queried for patients with primary HCV-associated HCC within Milan criteria who completed DAA therapy and underwent LT. Primary outcomes were HCC recurrence-free survival (RFS) and overall survival (OS). Secondary outcome was sustained virologic response (SVR) as indicator of efficacy of DAA therapy. Results: Of 857 patients, 753 met inclusion criteria. LDT consisted of radiofrequency ablation (RFA,13.3%,N=100), transarterial chemoembolization (TACE,44.1%,N=332), yttrium-90 (Y90,4.8%,N=36), and stereotactic body radiation therapy (SBRT,2.9%,N=22). Eighty-one(10.8%) patients received no LDT and 182(24.2%) received multiple modalities. SBRT patients had the highest 5-year RFS(100%) followed by those receiving TACE(94%), Y90(91.4%), RFA(89.9%), and multiple therapies(88.2%) (p=0.048, Figure 1A). OS was higher among patients who received SBRT, but not statistically significant (p=0.685, Figure 1B). SVR rate was lower among radiation-based therapy groups (Y90 73.5%, SBRT 78.9%, others≥88%; p=0.046). Conclusions: In a homogeneous population of HCV-associated HCC patients within Milan criteria who received bridging therapy while awaiting LT, SBRT was associated with increased RFS and trended towards increased OS. However, radiation-based therapy was associated with decreased efficacy of DAA as measured by lower SVR rates. The optimal choice of bridging therapy to liver transplant must balance oncologic and virologic outcomes, but these findings seem to favor SBRT.

Optimal Timing of Administration of Direct-acting Antivirals for Patients With Hepatitis C-associated Hepatocellular Carcinoma Undergoing Liver Transplantation.

To investigate the optimal timing of direct acting antiviral (DAA) administration in patients with hepatitis C-associated hepatocellular carcinoma (HCC) undergoing liver transplantation (LT). In patients with hepatitis C (HCV) associated HCC undergoing LT, the optimal timing of direct-acting antivirals (DAA) administration to achieve sustained virologic response (SVR) and improved oncologic outcomes remains a topic of much debate. The United States HCC LT Consortium (2015-2019) was reviewed for patients with primary HCV-associated HCC who underwent LT and received DAA therapy at 20 institutions. Primary outcomes were SVR and HCC recurrence-free survival (RFS). Of 857 patients, 725 were within Milan criteria. SVR was associated with improved 5-year RFS (92% vs 77%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 92%, and 82%, and 5-year RFS of 93%, 94%, and 87%, respectively. Among 427 HCV treatment-naïve patients (no previous interferon therapy), patients who achieved SVR with DAAs had improved 5-year RFS (93% vs 76%, P < 0.01). Patients who received DAAs pre-LT, 0-3 months post-LT, and ≥3 months post-LT had SVR rates of 91%, 93%, and 78% (P < 0.01) and 5-year RFS of 93%, 100%, and 83% (P = 0.01). The optimal timing of DAA therapy appears to be 0 to 3 months after LT for HCV-associated HCC, given increased rates of SVR and improved RFS. Delayed administration after transplant should be avoided. A prospective randomized controlled trial is warranted to validate these results.

Ligation-Mediated Polymerase Chain Reaction Detection of 8-Oxo-7,8-Dihydro-2'-Deoxyguanosine and 5-Hydroxycytosine at the Codon 176 of the p53 Gene of Hepatitis C-Associated Hepatocellular Carcinoma Patients.

Molecular mechanisms underlying Hepatitis C virus (HCV)-associated hepatocellular carcinoma (HCC) pathogenesis are still unclear. Therefore, we analyzed the levels of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and other oxidative lesions at codon 176 of the p53 gene, as well as the generation of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3H)-one deoxyguanosine (M1dG), in a cohort of HCV-related HCC patients from Italy. Detection of 8-oxodG and 5-hydroxycytosine (5-OHC) was performed by ligation mediated-polymerase chain reaction assay, whereas the levels of M1dG were measured by chromatography and mass-spectrometry. Results indicated a significant 130% excess of 8-oxodG at –TGC– position of p53 codon 176 in HCV-HCC cases as compared to controls, after correction for age and gender, whereas a not significant increment of 5-OHC at –TGC– position was found. Then, regression models showed an 87% significant excess of M1dG in HCV-HCC cases relative to controls. Our study provides evidence that increased adduct binding does not occur randomly on the sequence of the p53 gene but at specific sequence context in HCV-HCC patients. By-products of lipid peroxidation could also yield a role in HCV-HCC development. Results emphasize the importance of active oxygen species in inducing nucleotide lesions at a p53 mutational hotspot in HCV-HCC patients living in geographical areas without dietary exposure to aflatoxin B1.

Serum expression and diagnostic potential of long non-coding RNAs NEAT1 and TUG1 in viral hepatitis C and viral hepatitis C-associated hepatocellular carcinoma

BackgroundThe present study investigated the serum detectability and the diagnostic implications of long non-coding RNAs; nuclear enriched abundant transcript 1 (NEAT1) and taurine upregulated gene 1 (TUG1) in viral hepatitis C (HCV) and HCV-associated hepatocellular carcinoma (HCC). MethodsThe study included twenty healthy controls, forty non-malignant HCV patients and forty HCV-associated HCC patients. The study assessed liver function tests, the antioxidant status, serum alpha fetoprotein, p53, NEAT1 and TUG1. ResultsDiminished serum expression of NEAT1 and TUG1 was observed in HCV and HCV-associated HCC and was closely associated with deregulated liver function and elevated AFP levels. A model of NEAT1, TUG1 and AFP accurately differentiated between HCC patients and healthy controls with sensitivity greater than that of AFP alone. Additionally, the diagnostic performance of a model of TUG1, p53 and AFP was superior to that of each marker alone for predicting HCC in HCV patients. ConclusionSignificant alterations in the serum expression of NEAT1 and TUG1 in HCV and HCV-associated HCC patients were recorded. We propose NEAT1 and TUG1 as non-invasive, cost-effective and complementary biomarkers that improve the diagnostic characteristics of AFP.

Current noninvasive liver reserve models do not predict histological fibrosis severity in hepatocellular carcinoma

The Ishak scoring system has been used to stage liver fibrosis. Ten noninvasive liver reserve models were proposed to assess the severity of liver fibrosis, but their performance in hepatocellular carcinoma (HCC) is unknown. We aimed to evaluate the correlation between these models and severity of fibrosis in patients with HCC. A total 464 patients with HCC undergoing surgical resection were retrospectively analyzed. Multivariate logistic regression analysis was performed to determine independent factors associated with advanced fibrosis (Ishak score 4 or higher). There were no significant correlations between all noninvasive models and severity of fibrosis in HCC (p for trend all >0.1). In subgroup analysis, cirrhosis discriminant index (CDS) and Lok’s index in hepatitis B-, and fibrosis index based on 4 factors (FIB-4), CDS and Lok’s index in hepatitis C-associated HCC, best correlated with the severity of liver fibrosis. Low platelet count, prolonged prothrombin time, hepatitis C and multiple tumors were independently associated with advanced fibrosis. Among the 10 models, CDS was the best model to predict cirrhosis. Currently used noninvasive liver reserve models do not well correlate with severity of histological fibrosis in HCC. New noninvasive models are required to improve the predictive accuracy of liver fibrosis in HCC.

Impact of sustained viral response postcurative therapy of hepatitis C-related hepatocellular carcinoma: a systematic review and meta-analysis.

Antiviral therapy with interferon based therapies (IBT) has shown potential in improving survival in patients who have undergone resection or locoregional therapy for hepatitis C-associated hepatocellular carcinoma (HCV-HCC). However, this benefit has not been definitively ascribed to sustained viral response (SVR). Since IBT has been replaced with new directly acting agents (DAA), which are more efficacious in the treatment of HCV, we sought to better determine the prognostic impact of SVR in HCV-HCC. A systematic search of MEDLINE and EMBASE from inception through October 2015 was performed to identify studies that described the impact of presence of SVR in patients who underwent curative treatment of HCV-HCC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated for recurrence-free survival (RFS) and overall survival (OS) utilizing a random-effects model. After reviewing 858 abstracts, ten studies which included a total of 1,794 patients were selected and data was extracted. Of these ten studies, the impact of SVR on RFS and OS was reported in eight and seven studies respectively. In a meta-analysis which included 1,519 patients, SVR was associated with improved OS (HR 0.18; 95% CI 0.11-0.29, I2 =2%). We also found that SVR was associated with better RFS in a meta-analysis (1,241 patients; HR 0.50; 95% CI 0.40-0.63, I2 =0). In conclusion, SVR is associated with improved OS and RFS in patients with HCV who have undergone resection or locoregional therapy for HCC. Newer DAA therapies which offer increased tolerability and viral eradication should be considered as adjunctive therapy.

TCR gene-modified T cells can efficiently treat established hepatitis C-associated hepatocellular carcinoma tumors.

The success in recent clinical trials using T cell receptor (TCR)-genetically engineered T cells to treat melanoma has encouraged the use of this approach toward other malignancies and viral infections. Although hepatitis C virus (HCV) infection is being treated with a new set of successful direct anti-viral agents, potential for virologic breakthrough or relapse by immune escape variants remains. Additionally, many HCV+ patients have HCV-associated disease, including hepatocellular carcinoma (HCC), which does not respond to these novel drugs. Further exploration of other approaches to address HCV infection and its associated disease are highly warranted. Here, we demonstrate the therapeutic potential of PBL-derived T cells genetically engineered with a high-affinity, HLA-A2-restricted, HCV NS3:1406-1415-reactive TCR. HCV1406 TCR-transduced T cells can recognize naturally processed antigen and elicit CD8-independent recognition of both peptide-loaded targets and HCV+ human HCC cell lines. Furthermore, these cells can mediate regression of established HCV+ HCC in vivo. Our results suggest that HCV TCR-engineered antigen-reactive T cells may be a plausible immunotherapy option to treat HCV-associated malignancies, such as HCC.

SAT-284 - Active Antiviral Treatment for Chronic Hepatitis C Virus Infection Needs to be Recommended for Decreasing Hepatitis C-Associated Hepatocellular Carcinoma Risk in the New Era of Highly Effective Oral Antiviral Drugs

SAT-284 - Active Antiviral Treatment for Chronic Hepatitis C Virus Infection Needs to be Recommended for Decreasing Hepatitis C-Associated Hepatocellular Carcinoma Risk in the New Era of Highly Effective Oral Antiviral Drugs

Recurrent genetic alterations in hepatitis C-associated hepatocellular carcinoma detected by genomic microarray: a genetic, clinical and pathological correlation study.

BackgroundIn the US, approximately 50% of hepatocellular carcinoma (HCC) is caused by hepatitis-C virus (HCV) infection. The molecular mechanism of a malignant transformation of hepatocyte induced by HCV infection is still largely unclear. There are several clinical and pathological staging systems for HCC, but none of them include biological parameters as predictors for prognosis and there has not been a standardized molecular classification of HCC. To understand the underlying pathogenic genetic alterations in HCV-associated HCC and aid in molecular classification of HCC and patient prognosis, microarray analysis of DNA copy number alterations in HCC were conducted using whole genome microarray with DNA from formalin-fixed paraffin-embedded (FFPE) specimens of both cancer tissues and paired nearby cirrhotic non-neoplastic tissues.ResultsOur results show that the most common chromosomal aberrations (>5 Mb) observed in HCC were chromosomal gains of 1q (80%), 8q (60%), 7q (40%), 5p (33%), 7p (33%), Xq (33%), 5q (27%), and Xp (20%), as well as chromosome losses of 17p (40%), 4q21.21-q26 (33%), 8p (33%), 1p36.11-pter (20%), and 9p (20%). Statistically significant smaller copy number alterations (3.9 kb to 644 kb) were identified using STAC algorithm, including losses of FGFR3, RECQL4, NOTCH1, PTEN, TSC2, and/or ASPSCR1 and gains of ETV1and/or MAF. Correlation analysis between genetic data and pathological data showed that gain of 1q21.1-q23.2 and gain of 8q11.1q13.1 are significantly associated with grade 2–4 and moderately or poorly differentiated HCCs, and gain of chromosome 5q was significantly associated with HCCs with vascular invasion, while gain of chromosome 7q is significantly associated with stage I HCCs.ConclusionsThis study has provided a detailed map of genomic aberrations occurring in HCV-associated HCC and has suggested candidate genes. In addition, gene enrichment analysis on the recurrent abnormal regions indicated NF- kappaB and BMP signaling pathways in HCC development and progression. This study demonstrated that genomic microarray test can be used to distinguish HCC from non- neoplastic cirrhotic nodules and to identify prognostic factors associated with HCC progression using pathologically characterized FFPE samples. Our data support the utility of genomic microarray test for the diagnosis, risk stratification, and pathogenic studies of HCC.

B형간염 만연 지역에서 수술적 절제술을 시행한 C형간염 연관 간세포암 환자에서의 간경변 동반비율

B형간염 만연 지역에서 수술적 절제술을 시행한 C형간염 연관 간세포암 환자에서의 간경변 동반비율

Recurrent Genetic Alterations in Hepatitis C-Associated Hepatocellular Carcinoma Detected by Genomic Microarray and Their correlation with Histology and Clinical Outcome

Recurrent Genetic Alterations in Hepatitis C-Associated Hepatocellular Carcinoma Detected by Genomic Microarray and Their correlation with Histology and Clinical Outcome

Prognostic Value of Serum AFP, AFP-L3, and GP73 in Monitoring Short-term Treatment Response and Recurrence of Hepatocellular Carcinoma after Radiofrequency Ablation

Alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), and Golgi protein 73 (GP73) levels have been widely used as tumor markers for the diagnosis of hepatocellular carcinoma (HCC). The aim of this study was to investigate whether these tumor markers could be used to monitor short-term treatment response and recurrence of HCC in patients undergoing radiofrequency ablation (RFA). Between July 2012 and July 2013, 53 consecutive patients with newly diagnosed HCC were prospectively enrolled in this study. Among these, 32 patients underwent RFA, after which they were followed up prospectively at the First Hospital of Jilin University in China. AFP, AFP-L3, and GP-73 values pre-RFA were not associated with tumor size, whereas AFP and GP-73 levels tended to be associated with tumor number, the presence of vascular invasion, deterioration of liver function, advanced-stage disease, and a poor performance status. GP-73 levels were dramatically elevated in the patients with hepatitis C-associated HCC. Neither pre-RFA nor 1-month post-RFA tumor marker values were associated with short-term outcome. The short-term recurrence rate of AFP-positive patients measured 1 month post-RFA was obviously higher than that of AFP-negative patients. AFP and GP-73 values were associated with clinical variables representing tumor growth and invasiveness, and the AFP value measured 1 month post-RFA was a strong predictor of short-term recurrence in patients with HCC.

Impact of PNPLA3 polymorphisms on the development of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

The PNPLA3 rs738409 C>G polymorphism (encoding for I148M) has recently been identified as a susceptibility factor for steatosis-mediated liver damage. We evaluated the influence of this polymorphism on hepatocarcinogenesis in patients with chronic hepatitis C (CHC) virus infection. We genotyped the rs738409 single nucleotide polymorphism in 358 hepatitis C-associated hepatocellular carcinoma (HCC) patients and correlated the age at onset of HCC and the interval between hepatitis C virus (HCV) infection and the development of HCC in patients with each genotype. The frequencies of CC, CG and GG genotypes were 27.9% (100/358), 49.2% (176/358) and 22.9% (82/358), respectively, and were in Hardy-Weinberg equilibrium. The median age at onset of HCC for the GG genotype was significantly younger compared to for non-GG genotypes (67.81 vs 69.87 years, P < 0.001), and the median interval between HCV infection and the development of HCC was significantly shorter in patients with the GG genotype (39.96 vs 40.85 years, P = 0.008). PNPLA3 GG genotype was also associated with a higher aspartate aminotransferase level (69.5 vs 59.0 IU/L, P = 0.02), lower prothrombin time (73.0% vs 78.0%, P = 0.008) and a higher prevalence of histological steatosis (40.0% vs. 22.2%, P = 0.01) at the time of HCC onset. The PNPLA3 genotype GG may be associated with accelerated hepatocarcinogenesis in CHC patients through increased steatosis in the liver.

IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients. We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype. Frequencies of TT, TG, and GG genotypes were 74.3% (261/351), 24.8% (87/351), and 0.9% (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P=0.02) in males (P<0.001) with higher body mass index (BMI; P=0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7vs. 58.6%; P=0.01), lower AST (69.1 vs. 77.7IU/L, P=0.02), lower ALT (67.8 vs. 80.9IU/L, P=0.002), higher platelet count (12.8 vs. 11.2×10(4)/μL, P=0.002), and higher prothrombin time (79.3 vs. 75.4%, P=0.002). The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.

Survival in Liver Transplant Recipients with Hepatitis B- or Hepatitis C-Associated Hepatocellular Carcinoma: The Chinese Experience from 1999 to 2010

BackgroundHepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and hepatitis C virus (HCV)-HCC are the main indications for liver transplantation. We compared differences in survival outcomes between these two conditions.Methods and FindingsThe China Liver Transplant Registry (CLTR) contains data collated from all transplants performed in 86 liver transplantation centers across China. We analyzed CLTR data from January 1999 to December 2010. In all, 7,658 patients (7,162 with HBV-HCC and 496 with HCV-HCC) were included in this study. Clinical characteristics were compared between the HBV-HCC and HCV-HCC groups; Kaplan–Meier analysis was used to calculate the overall, tumor-free and hepatitis-free survival rates. The 1-year, 3-year and 5-year overall survival was significantly higher in HBV-HCC recipients than in HCV-HCC recipients (76.65%, 56.61% and 49.10% vs. 64.59%, 42.78% and 39.20%, respectively; P<0.001). The corresponding tumor-free survival rates (63.55%, 47.37%, 40.99% vs. 56.84%, 38.04%, 35.66%, respectively) and hepatitis-free survival rates (75.49%, 54.84%, 47.34% vs. 63.87%, 42.15%, 39.33%, respectively) were both superior in HBV-HCC recipients (both P<0.001). Multivariate analyses identified hepatitis, preoperative alpha-fetoprotein (AFP) level, size of largest tumor, number of tumor nodules, TNM stage, vascular invasion and preoperative model for end-stage liver disease (MELD) score as independent predictors of overall, tumor-free and hepatitis-free survival.ConclusionsSurvival outcomes after liver transplantation were significantly better in HBV-HCC patients than in HCV-HCC patients. This finding may be used to guide donor liver allocation in transplantation programs.

Abstract 1150: Biomarkers discovery and racial disparity in hepatitis C-associated hepatocellular carcinoma.

Abstract Cancer health disparities represent a major public health concern in the US. Even when factors such as socioeconomic status, carcinogen exposure, and access to care are accounted for, disparities persist in the form of higher overall incidence rates and worse clinical outcomes for minority populations than for overall population. A case of point is the racial disparities in liver cancer-related mortality. Hepatitis C virus (HCV) is the most significant contributing factor in the development of hepatocellular carcinoma (HCC). In the US, African Americans (AAs) have twice the prevalence of HCV/genotype 1 infection, and develop HCC at more than twice the rate as Caucasian (CA) counterparts. African Americans are, however, less likely to respond to interferon-based therapy than CAs, and have considerably lower likelihood of receiving liver transplantation. While it is evident that viral infection with HCV is associated with the development of HCC, there are critical gaps in our understanding of the biological basis for this racial disparity. The aim of the current study was to define the molecular signatures of HCV disease progression in liver &amp; tumor tissue samples obtained from AA &amp; CA patients using 8-plex iTRAQ-based proteomics coupled with bioinformatics data analyses. The raw data were analyzed by the ProteinPilot v3.0 using the paragon algorithm. Searches were performed against a comprehensive database generated from SwissPort, Refseq, and Tremble protein sequences. The data were normalized for loading error &amp; background correction. The proteins with confidence score &amp;gt; 90% and with at least 1 peptide of 95% identification confidence were used for further quality control &amp; differential expression analysis. The quality control analysis was performed using pairwise correlation plots, boxplots, principal component analysis (PCA), and unsupervised hierarchical clustering. Supervised analysis was performed to identify differentially expressed proteins (DEP), where the relative protein expression values were compared between groups (Normal vs. Cirrhosis (CIR), Normal vs. HCC, CIR vs. HCC). Based on our experimental design, 787 unique proteins were identified. Of those, 32 were differentially expressed between normal, cirrhosis &amp; HCC groups. Targets validation using real-time PCR (RT-PCR) or western blotting (WB) shows racially distinct alteration in the expression of certain targets. For example, the mRNA expression levels of TF were 2 and18-fold higher in CIR &amp; HCC, respectively in AAs compared to CAs. Similarly, the expression of APOA1 mRNA levels was 7-fold higher in HCC of AAs compared to CAs. This trend was similar to their protein expression levels using WB. However, the level of HNF4α protein was down regulated in AAs compared to CAs. This indicates that HNF4α does not regulate TF &amp; APOA1 expression in HCC of AA samples. Citation Format: Simon T. Dillon, Manoj K. Bhasin, Xiaoxing (Stella) Feng, David Koh, Sayed Salih Daoud. Biomarkers discovery and racial disparity in hepatitis C-associated hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1150. doi:10.1158/1538-7445.AM2013-1150

Recurrent Genetic Alterations in Hepatitis C-associated Hepatocellular Carcinoma Detected by CGH+SNP Array

Recurrent Genetic Alterations in Hepatitis C-associated Hepatocellular Carcinoma Detected by CGH+SNP Array