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

Journal of Gastroenterology volume 51, pages 473–486 (2016)Cite this article

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.

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Fig. 1
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Abbreviations

HCC:

Hepatocellular carcinoma

TERT :

Telomerase reverse transcriptase

HCV:

Hepatitis C virus

HBV:

Hepatitis B virus

HBsAg:

Hepatitis B surface antigen

PCR:

Polymerase chain reaction

ISPs:

Ion sphere particles

COSMIC:

Catalogue of somatic mutations in cancer

gDNA:

Genomic DNA

CT:

Computed tomography

MRI:

Magnetic resonance imaging

AFP:

Alpha-fetoprotein

DFS:

Disease-free survival

OS:

Overall survival

Anti-HBc:

Antibody to hepatitis B core antigen

Anti-HBs:

Antibody to hepatitis B surface antigen

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Author notes

    Affiliations

    1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

      Fukiko Kawai-Kitahata, Yasuhiro Asahina, Sei Kakinuma, Miyako Murakawa, Sayuri Nitta, Takako Watanabe, Satoshi Otani, Miki Taniguchi, Fumio Goto, Hiroko Nagata, Shun Kaneko, Megumi Tasaka-Fujita, Yuki Nishimura-Sakurai, Seishin Azuma, Yasuhiro Itsui, Mina Nakagawa & Mamoru Watanabe

    2. Department of Liver Disease Control, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

      Yasuhiro Asahina & Sei Kakinuma

    3. Department of Molecular Oncology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

      Shinji Tanaka

    4. Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan

      Minoru Tanabe

    5. First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, 1110 Shimogato, Chuo-shi, Yamanshi, 409-3898, Japan

      Shinichi Takano, Mitsuharu Fukasawa, Minoru Sakamoto, Shinya Maekawa & Nobuyuki Enomoto

    Authors
    1. Fukiko Kawai-Kitahata
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    2. Yasuhiro Asahina
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    13. Megumi Tasaka-Fujita
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    18. Minoru Tanabe
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    Corresponding author

    Correspondence to Yasuhiro Asahina.

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    Conflict of interest

    Dr. Asahina and Dr. Kakinuma belong to a donation-funded department funded by Chugai Pharmaceutical Co. Ltd., Toray Industries Inc., Bristol-Myers Squibb, Dainippon Sumitomo Pharma Co. Ltd., and Merck Sharp & Dohme. The others have nothing to disclose.

    Financial Support

    This study was supported by grants from the Japanese Ministry of Education, Culture, Sports, Science, and Technology; the Japanese Ministry of Welfare, Health, and Labor; the Japan Society for the Promotion of Science; and the Japan Health Sciences Foundation.

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    Cite this article

    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 51, 473–486 (2016). https://doi.org/10.1007/s00535-015-1126-4

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    • DOI: https://doi.org/10.1007/s00535-015-1126-4

    Keywords

    • TERT
    • TP53
    • CTNNB1