Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver.


METHODS
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 one of the mutated genes.


RESULTS
Whole exome sequencing showed 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 nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice.


CONCLUSIONS
Based on analysis of liver tissue 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.
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Atsuyuki
A
Ikeda
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Takahiro
T
Shimizu
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yuko
Y
Matsumoto
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yosuke
Y
Fujii
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Yuji
Y
Eso
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tadashi
T
Inuzuka
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Aya
A
Mizuguchi
Department of Nanobio Drug Discovery, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
Kazuharu
K
Shimizu
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Etsuro
E
Hatano
Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Shinji
S
Uemoto
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Tsutomu
T
Chiba
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: maru@kuhp.kyoto-u.ac.jp.
Hiroyuki
H
Marusawa
D000328:Adult; D000368:Aged; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D019698:Hepatitis C, Chronic / Q000150:complications / Q000235:genetics*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications / Q000235:genetics*; D008113:Liver Neoplasms / Q000150:complications / Q000235:genetics*; D008114:Liver Neoplasms, Experimental / Q000235:genetics*; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D054411:Receptors, Leptin / Q000235:genetics*
D054411:Receptors, Leptin
AID; Genetics; HCC; HCV; Ig; Liver Cancer; STAT3; TAA; Whole Exome Sequencing; activation-induced cytidine deaminase; hepatitis C virus; hepatocellular carcinoma; immunoglobulin; thioacetamide