Journal Article

Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features

Kaneko, Shun, Nishimura-Sakurai, Yuki, Itsui, Yasuhiro, Enomoto, Nobuyuki, Watanabe, Mamoru, Goto, Fumio, Watanabe, Takako, Azuma, Seishin, Kawai-Kitahata, Fukiko, Otani, Satoshi, Asahina, Yasuhiro, Tasaka-Fujita, Megumi, Nakagawa, Mina, Tanaka, Shinji, Nagata, Hiroko, Tanabe, Minoru, Kakinuma, Sei, Nitta, Sayuri, Takano, Shinichi, Sakamoto, Minoru, Murakawa, Miyako, Fukasawa, Mitsuharu, Maekawa, Shinya, Taniguchi, Miki

2016

Overview

Background and Aims Genetic alterations in specific genes are critical events in carcinogenesis and hepatocellular carcinoma (HCC) progression. However, the genetic alterations responsible for HCC development, progression, and survival are unclear. Methods We investigated the essential difference in genetic alterations between HCC and adjacent non-HCC tissues using next-generation sequencing technology. Results We found recurrent mutations in several genes such as telomerase reverse transcriptase ( TERT ; 65 % of the total 104 HCCs), TP53 (38 %), CTNNB1 (30 %), AXIN1 (2 %), PTEN (2 %), and CDKN2A (2 %). TERT promoter mutations were associated with older age ( p  = 0.005), presence of hepatitis C virus (HCV) infection ( p  = 0.003), and absence of hepatitis B virus (HBV) infection ( p  < 0.0001). In hepatitis B surface antigen (HBs Ag)-positive HCC without TERT promoter mutations, HBV integration into TERT locus was found in 47 % patients and was mutually exclusive to TERT promoter mutations. Most (89 %) HBV integrants were in the HBx region. TP53 mutations were associated with HBV infection ( p  = 0.0001) and absence of HCV infection ( p  = 0.002). CTNNB1 mutations were associated with absence of HBV infection ( p  = 0.010). Moreover, TERT promoter mutation was significantly associated with shorter disease-free survival ( p  = 0.005) and poor overall survival ( p  = 0.024). Conclusions Gene alterations in TERT promoter, TP53 , CTNNB1 , and HBV integration were closely associated with HCC development, and mutations in TERT promoter are related to poor prognosis. These results are useful for understanding the underlying mechanism of hepatocarcinogenesis, diagnosis, and predicting outcomes of patients with HCC.

• Publisher: Springer Japan,Springer,Springer Nature B.V
• Subject: Abdominal Surgery / Adult / Aged / Aged, 80 and over / Analysis / beta Catenin - genetics / Biliary Tract / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - pathology / Carcinoma, Hepatocellular - virology / Colorectal Surgery / Development and progression / Disease-Free Survival / Female / Follow-Up Studies / Gastroenterology / Health aspects / Hepatitis B / Hepatitis B - complications / Hepatitis B Surface Antigens - blood / Hepatitis B virus / Hepatitis C - complications / Hepatitis C virus / Hepatology / Hepatoma / High-Throughput Nucleotide Sequencing / Humans / Infection / Liver Neoplasms - genetics / Liver Neoplasms - pathology / Liver Neoplasms - virology / Male / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Middle Aged / Mutation / Original Article—Liver / Pancreas / Promoter Regions, Genetic / Surgical Oncology / Survival Rate / Telomerase / Telomerase - genetics / Tumor proteins / Tumor Suppressor Protein p53 - genetics / Virus Integration