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Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features.
J Gastroenterol. 2016 May; 51(5):473-86.JG

Abstract

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.

Authors+Show Affiliations

Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.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.Department of Molecular Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.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.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan.Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26553052

Citation

Kawai-Kitahata, Fukiko, et al. "Comprehensive Analyses of Mutations and Hepatitis B Virus Integration in Hepatocellular Carcinoma With Clinicopathological Features." Journal of Gastroenterology, vol. 51, no. 5, 2016, pp. 473-86.
Kawai-Kitahata F, Asahina Y, Tanaka S, et al. Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. J Gastroenterol. 2016;51(5):473-86.
Kawai-Kitahata, F., Asahina, Y., Tanaka, S., Kakinuma, S., Murakawa, M., Nitta, S., Watanabe, T., Otani, S., Taniguchi, M., Goto, F., Nagata, H., Kaneko, S., Tasaka-Fujita, M., Nishimura-Sakurai, Y., Azuma, S., Itsui, Y., Nakagawa, M., Tanabe, M., Takano, S., ... Watanabe, M. (2016). Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. Journal of Gastroenterology, 51(5), 473-86. https://doi.org/10.1007/s00535-015-1126-4
Kawai-Kitahata F, et al. Comprehensive Analyses of Mutations and Hepatitis B Virus Integration in Hepatocellular Carcinoma With Clinicopathological Features. J Gastroenterol. 2016;51(5):473-86. PubMed PMID: 26553052.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Comprehensive analyses of mutations and hepatitis B virus integration in hepatocellular carcinoma with clinicopathological features. AU - Kawai-Kitahata,Fukiko, AU - Asahina,Yasuhiro, AU - Tanaka,Shinji, AU - Kakinuma,Sei, AU - Murakawa,Miyako, AU - Nitta,Sayuri, AU - Watanabe,Takako, AU - Otani,Satoshi, AU - Taniguchi,Miki, AU - Goto,Fumio, AU - Nagata,Hiroko, AU - Kaneko,Shun, AU - Tasaka-Fujita,Megumi, AU - Nishimura-Sakurai,Yuki, AU - Azuma,Seishin, AU - Itsui,Yasuhiro, AU - Nakagawa,Mina, AU - Tanabe,Minoru, AU - Takano,Shinichi, AU - Fukasawa,Mitsuharu, AU - Sakamoto,Minoru, AU - Maekawa,Shinya, AU - Enomoto,Nobuyuki, AU - Watanabe,Mamoru, Y1 - 2015/11/09/ PY - 2015/06/05/received PY - 2015/09/19/accepted PY - 2015/11/11/entrez PY - 2015/11/11/pubmed PY - 2017/1/18/medline KW - CTNNB1 KW - TERT KW - TP53 SP - 473 EP - 86 JF - Journal of gastroenterology JO - J. Gastroenterol. VL - 51 IS - 5 N2 - 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. SN - 1435-5922 UR - https://www.unboundmedicine.com/medline/citation/26553052/Comprehensive_analyses_of_mutations_and_hepatitis_B_virus_integration_in_hepatocellular_carcinoma_with_clinicopathological_features_ L2 - https://dx.doi.org/10.1007/s00535-015-1126-4 DB - PRIME DP - Unbound Medicine ER -