Leptin Receptor Somatic Mutations Are Frequent in HCV-Infected Cirrhotic Liver and Associated With Hepatocellular Carcinoma
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Gastroenterology
(Impact Factor: 16.72).
09/2013; 146(1). DOI: 10.1053/j.gastro.2013.09.025
Hepatocellular carcinoma (HCC) develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of HCC development in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in non-tumor cirrhotic liver.
We determined the whole-exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole-exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for 1 of the mutated genes.
Whole-exome sequencing demonstrated that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and non-tumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) non-tumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of signal transducer and activator of transcription 3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors following administration of thioacetamide, compared with none of the control mice.
Based on analysis of liver tissues samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis.
Available from: Kalyani Mondal
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ABSTRACT: Hepatocellular carcinoma (HCC), one of the leading causes of cancer-related death, develops from premalignant lesions in chronically damaged livers. While it is well-established that FGF19 acts through receptor complex FGFR4-β-Klotho (KLB) to regulate bile acid metabolism, FGF19 is also implicated in the development of HCC. In humans, FGF19 is amplified in HCC and its expression is induced in the liver under cholestatic and cirrhotic conditions. In mice, ectopic overexpression of FGF19 drives HCC development in a process that requires FGFR4. In this study, we describe an engineered FGF19 variant (M70) which fully retains bile acid regulatory activity but does not promote HCC formation, demonstrating that regulating bile acid metabolism is distinct and separable from tumor-promoting activity. Mechanistically, we show that FGF19 stimulates tumor progression by activating the STAT3 pathway, an activity eliminated by M70. Furthermore, M70 inhibits FGF19-dependent tumor growth in a rodent model. Our results suggest that selectively targeting the FGF19-FGFR4 pathway may offer a tractable approach to improve the treatment of chronic liver disease and cancer.
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Virus-induced hepatocarcinogenesis involves a series of histological developmental processes with the stepwise acquisition of several genetic changes that are necessary for the malignant transformation of hepatocytes. Although genetic alterations are known to be involved in the pathogenesis of hepatocellular carcinoma (HCC), little is known about the contributions of specific genes to this process. To gain insight into the genetic alterations involved in the neoplastic evolution from chronic hepatitis B virus infection to dysplastic nodules (DN) to HCC, we captured and sequenced the exomes of four DNA samples: one DN sample, two HCC samples, and one control peripheral blood sample from a single HCC patient. Mutations in the UBE3C gene (encoding ubiquitin ligase E3C) were observed in both tumor tissues. Then we resequenced the UBE3C gene in a cohort of 105 HCC patients and identified mutations in 17 out of a total of 106 (16.0%) HCC patients. The subsequent experiments showed that UBE3C promoted HCC progression by regulating HCC cells epithelial-mesenchymal transition. Clinically, a tissue microarray study of a cohort containing 323 HCC patients revealed that the overexpression of UBE3C in primary HCC tissues correlated with decreased survival (hazard ratio [HR] =1.657, 95% confidence interval [CI] =1.220-2.251, P=0.001) and early tumor recurrence (HR=1.653, 95% CI=1.227-2.228, P=0.001) in postoperative HCC patients.
Our findings indicate that UBE3C is a candidate oncogene involved in tumor development and progression and therefore a potential therapeutic target in applicable HCC patients.
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Recently, a number of studies have performed genome or exome sequencing of hepatocellular carcinoma (HCC) and identified hundreds or even thousands of mutations in protein-coding genes. However, these studies have only focused on a limited number of candidate genes, and many important mutation resources remain to be explored.
In this study, we integrated mutation data obtained from various sources and performed pathway and network analysis. We identified 113 pathways that were significantly mutated in HCC samples and found that the mutated genes included in these pathways contained high percentages of known cancer genes, and damaging genes and also demonstrated high conservation scores, indicating their important roles in liver tumorigenesis. Five classes of pathways that were mutated most frequently included (a) proliferation and apoptosis related pathways, (b) tumor microenvironment related pathways, (c) neural signaling related pathways, (d) metabolic related pathways, and (e) circadian related pathways. Network analysis further revealed that the mutated genes with the highest betweenness coefficients, such as the well-known cancer genes TP53, CTNNB1 and recently identified novel mutated genes GNAL and the ADCY family, may play key roles in these significantly mutated pathways. Finally, we highlight several key genes (e.g., RPS6KA3 and PCLO) and pathways (e.g., axon guidance) in which the mutations were associated with clinical features.
Our workflow illustrates the increased statistical power of integrating multiple studies of the same subject, which can provide biological insights that would otherwise be masked under individual sample sets. This type of bioinformatics approach is consistent with the necessity of making the best use of the ever increasing data provided in valuable databases, such as TCGA, to enhance the speed of deciphering human cancers.
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