home > bioproject > PRJDB1838
identifier PRJDB1838
type bioproject
sra-study  DRP000901
organism Homo sapiens
title Somatic mutations accumulated in leptin receptor during development of hepatitis C-associated hepatocellular carcinoma
description Background & Aims: Hepatocellular carcinoma (HCC) arises in chronic hepatitis and/or cirrhosis via a stepwise accumulation of genetic alterations in various genes. To explore the genetic basis of HCC developed in the hepatitis C virus (HCV)-associated chronic liver disease, we focused on the genetic aberrations latently accumulated in the non-tumorous chronically-inflamed liver. Methods: We determined the whole exome sequences of the 7 paired tumor and the non-tumorous livers. Additional deep sequencing of the representative tumor-related genes and the mutated genes identified were performed on the 22 cirrhotic livers. Functional study of the mutated gene was carried out in vitro and in vivo.Results: Whole exome sequencing clarified that somatic mutations are accumulated in various genes in HCV-infected inflamed liver tissues. Among the mutated genes identified, leptin receptor (LEPR) gene was most recurrently mutated in both tumor and non-tumorous cirrhotic liver tissues. Deep sequencing analyses determined that the LEPR mutations were detectable in 12/22 (54.5%) non-tumorous cirrhotic liver. In vitro downstream validation study demonstrated that the 4/7 mutations determined in the LEPR gene of the cirrhotic livers resulted in the reduction in the levels of signal transducer and activator of transcription 3 phosphorylation, causing the inactivation of LEPR-mediated signaling. Moreover, the LEPR deficient C57BL/KsJ-db/db mice showed higher sensitivity to thioacetamide-mediated liver tumorigenesis compared with control mice.Conclusion: These findings provided the novel evidence showing that somatic mutations are latently accumulated in LEPR in the inflamed liver with chronic HCV infection, providing the putative genesis that enhances the susceptibility for hepatocarcinogenesis.
data type DDBJ SRA Study
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