Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

OBJECTIVE: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. DESIGN: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. RESULTS: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-ßcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes. CONCLUSION: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Hepatocellular Carcinoma in Mongolia Delineates Unique Molecular Traits and a Mutational Signature Associated with Environmental Agents.

PURPOSE: Mongolia has the world's highest incidence of hepatocellular carcinoma (HCC), with ∼100 cases/100,000 inhabitants, although the reasons for this have not been thoroughly delineated. EXPERIMENTAL DESIGN: We performed a molecular characterization of Mongolian (n = 192) compared with Western (n = 187) HCCs by RNA sequencing and whole-exome sequencing to unveil distinct genomic and transcriptomic features associated with environmental factors in this population. RESULTS: Mongolian patients were younger, with higher female prevalence, and with predominantly HBV-HDV coinfection etiology. Mongolian HCCs presented significantly higher rates of protein-coding mutations (121 vs. 70 mutations per tumor in Western), and in specific driver HCC genes (i.e., APOB and TSC2). Four mutational signatures characterized Mongolian samples, one of which was novel (SBS Mongolia) and present in 25% of Mongolian HCC cases. This signature showed a distinct substitution profile with a high proportion of T>G substitutions and was significantly associated with a signature of exposure to the environmental agent dimethyl sulfate (71%), a 2A carcinogenic associated with coal combustion. Transcriptomic-based analysis delineated three molecular clusters, two not present in Western HCC; one with a highly inflamed profile and the other significantly associated with younger female patients. CONCLUSIONS: Mongolian HCC has unique molecular traits with a high mutational burden and a novel mutational signature associated with genotoxic environmental factors present in this country.

The genomic landscape of Mongolian hepatocellular carcinoma.

Mongolia has the highest incidence of hepatocellular carcinoma (HCC) in the world, but its causative factors and underlying tumor biology remain unknown. Here, we describe molecular characteristics of HCC from 76 Mongolian patients by whole-exome and transcriptome sequencing. We present a comprehensive analysis of mutational signatures, driver genes, and molecular subtypes of Mongolian HCC compared to 373 HCC patients of different races and ethnicities and diverse etiologies. Mongolian HCC consists of prognostic molecular subtypes similar to those found in patients from other areas of Asia, Europe, and North America, as well as other unique subtypes, suggesting the presence of distinct etiologies linked to Mongolian patients. In addition to common driver mutations (TP53, CTNNB1) frequently found in pan-cancer analysis, Mongolian HCC exhibits unique drivers (most notably GTF2IRD2B, PNRC2, and SPTA1), the latter of which is associated with hepatitis D viral infection. These results suggest the existence of new molecular mechanisms at play in Mongolian hepatocarcinogenesis.

Open-label Phase II clinical trial in 75 patients with advanced hepatocellular carcinoma receiving daily dose of tableted liver cancer vaccine, hepcortespenlisimut-L.

BACKGROUND: An increasing number of studies is now devoted to immunotherapy of cancer. We evaluated the clinical benefit of hepcortespenlisimut-L (Hepko-V5 [formerly known as V5])-an oral therapeutic vaccine designated by the United States Food and Drug Administration (FDA) as an orphan drug for treatment of hepatocellular carcinoma (HCC). V5 was initially developed by us in 2002 to treat hepatitis B or C viral infections and liver cirrhosis. METHODS: The outcome of open-label Phase II trial of daily dose of V5 pill was analyzed retrospectively. Over a period of 5 years, 75 patients with advanced HCC were enrolled, consisting of 29 (38.7%) females and 46 (61.3%) males with a median age of 60 years (mean 61.6±8.1 years). Out of these, 23 (30.7%) had hepatitis B and 34 (45.3%) had hepatitis C infections, including 9 (12%) with dual infection, 4 (5.3%) negative for both viruses, and 5 (6.7%) without established viral diagnosis. Most patients (94.7%) had underlying liver cirrhosis of varying severity. RESULTS: After a median of 2 months of treatment, 50 out of 75 patients had experienced a decline in serum levels of the tumor marker, alpha-fetoprotein (AFP) (66.7%; P=0.006 by Wilcoxon signed rank test). Baseline median AFP levels were 245.2 IU/mL (mean 4,233; range 7.2-92,407; 95% confidence interval [CI] 1,186-7,280) and post-treatment values were 102.3 IU/mL (mean 2,539; range 0.9-54,478; 95% CI 503-4,575). The decrease in AFP was correlated either with tumor clearance or regression on computed tomography scans. The median overall survival time could not be established since 68 out of 75 (90.7%) patients were still alive after median follow-up of 12 months (mean 15±9.7; range 7-59; 95% CI 12.8-17.2). The first patient in this study received immunotherapy 5 years ago and still remains in complete remission. None of the patients experienced any serious adverse effects or toxicity. CONCLUSION: The results indicate that hepcortespenlismut-L is a safe, effective, and fast-acting immunomodulatory intervention for HCC. The Phase III, randomized, double-blind, placebo-controlled trial is now initiated at the Mongolian National Cancer Center to confirm these promising findings.

Impact of Glissonean pedicle approach for centrally located hepatocellular carcinoma in mongolia.

Approaches to surgical resection of centrally located HCC remain controversial. Traditionally, hemi- or extended hepatectomy is suggested. However, it carries a high risk of postoperative complications in patients with cirrhosis. An alternative approach is Glissonean pedicle transection method. This study was conducted to assess the surgical and survival outcomes associated with central liver resection using the Glissonean pedicle transection. Sixty-nine patients with centrally located HCC were studied retrospectively. They were divided into conventional approach group with hemi- or extended hepatectomy, and Glissonean approach group with multisegmental central liver resection using the Glissonean pedicle transection. Glissonean pedicle transection method has comparable or superior surgical and survival outcomes to conventional hemi- or extended hepatectomy with regard to intraoperative bleeding, complications, hospital stay, and postoperative mortality and survival outcomes in patients with centrally located HCC. The 1-, 3-, and 5-year overall survival rates of the conventional approach group were 74%, 64%, and 55% respectively. For the Glissonean approach group, the 1 and 3-year overall survival rates were 86% and 61%, respectively. Glissonean pedicle transection method is a safe and effective surgical procedure in patients with centrally located HCC.

Status quo of chronic liver diseases, including hepatocellular carcinoma, in Mongolia.

Because Mongolia has much higher liver disease burden than any other regions of the world, it is necessary to provide information on real-time situation of chronic liver disease in Mongolia. In this article, we reviewed studies performed in Mongolia from 2000 to 2011 on seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) among healthy individuals and patients with chronic liver diseases, and on the practice patterns for the management of liver cirrhosis and hepatocellular carcinoma (HCC). According to previous reports, the seroprevalence of HBV and HCV in general population in Mongolia is very high (11.8% and 15% for HBV and HCV, respectively). Liver cirrhosis is also highly prevalent, and mortality from liver cirrhosis remained high for the past decade (about 30 deaths per 100,000 populations per year). Among patients with cirrhosis, 40% and 39% are positive for HBsAg and anti-HCV, respectively, and 20% are positive for both. The seroprevalence is similar for HCC and more than 90% of HCC patients are positive for either HBV or HCV. The incidence of HCC in Mongolia is currently among the highest in the world. The mortality from HCC is also very high (52.2 deaths per 100,000 persons per year in 2010). Partly due to the lack of established surveillance systems, most cases of HCC are diagnosed at an advanced stage. The mortality from liver cirrhosis and HCC in Mongolia may be reduced by implementation of antiviral therapy program and control of alcohol consumption.