title: Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Fukiko
authors.initials: F
authors.lastname: Kawai-Kitahata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. asahina.gast@tmd.ac.jp.|Department of Liver Disease Control, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. asahina.gast@tmd.ac.jp.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Asahina
authors.affiliation: Department of Molecular Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.|Department of Liver Disease Control, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Sei
authors.initials: S
authors.lastname: Kakinuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Miyako
authors.initials: M
authors.lastname: Murakawa
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Nitta
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Otani
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Taniguchi
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Goto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagata
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Kaneko
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Tasaka-Fujita
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura-Sakurai
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Seishin
authors.initials: S
authors.lastname: Azuma
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Itsui
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Mina
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takano
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Fukasawa
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Sakamoto
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Maekawa
authors.affiliation: First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Enomoto
authors.affiliation: Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology* / Q000821:virology; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006509:Hepatitis B / Q000150:complications*; D006514:Hepatitis B Surface Antigens / Q000097:blood; D006526:Hepatitis C / Q000150:complications*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D016662:Virus Integration; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D006514:Hepatitis B Surface Antigens; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C509186:TERT protein, human; D019098:Telomerase
keywords: CTNNB1; TERT; TP53