Search for novel genomic regions related to liver carcinogenesis by using a hepatitis B virus integration site as a genetic probe

• Project/Area Number: 18590742
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: MINAMI Masahito Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Research Associate (60326220)
• Co-Investigator(Kenkyū-buntansha): 岡上 武 京都府立医科大学, 医学研究科, 教授 (20150568)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥3,790,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥390,000); Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2006: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: hepatitis B virus / integration / liver carcinogenesis / hTERT / MLL4

Research Abstract

Human genomic regions flanking integrated hepatitis B virus (HBV) were investigated from liver tissues of chronic hepatitis, liver cancers and non-cancerous tissues surrounding liver cancers. We developed an HBV-Alu PCR method to efficiently amplify the viral-host junctions. From 26 cases with chronic hepatitis and 10 with liver cancer, 75 viral-host junctions were cloned and genomic sequences were determined. Together with genomic database search and our results, we could identify a human telomerase reverse transcriptase (hTERT) gene and MLL4 gene as common integration sites. These two genes were found integrated exclusively in liver cancer tissues. HBV integration into an hTERT gene was found in about 5 % of liver cancer cases where HBV integration sites were investigated.
To investigate when the integration into hTERT occur during chronic HBV infection, we searched for HBV-hTERT chimeric sequences in chronic hepatitis tissues by PCR with several primer sets, but no HBV-hTERT chimeras were detected. Thus it is suggested that HBV integration into the hTERT gene occurs in more advanced stages of HBV infection than chronic hepatitis.

Research Products

• [Journal Article] Management of HBV infection in Japan (2007)
  • Author(s): Minami M, Okanoue T.
  • Journal Title: Hepatology Research 37(s1)
  • NAID: 10019566326
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy (2007)
  • Author(s): Matsumoto A, Tanaka E, Minami M, Okanoue T, Yatsuhashi H, Nagaoka S, Suzuki F, Kobayashi M, Chayama K, Imamura M, Yotsuyanagi H, Nakaoka S, Maki N, Kawata S, Kumada H, Iino S, Kiyosawa K.
  • Journal Title: Hepatology Research 37(8) Pages: 661-666
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Management of HBV infection(in Japan) (2007)
  • Author(s): Minami, M., Okanoue, T
  • Journal Title: Hepatology Research 37(s1) Pages: 579-882
  • NAID: 10019566326
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy (2007)
  • Author(s): Matsumoto, A., Tanaka, E., Minami, M., Okanoue, T., Yatsuhashi, H., Nagaoka, S., Suzuki, F., Kobayashi, M., Chayama, K., Imamura, M., Yotsuyanagi, H., Nakaoka, S., Maki, N., Kawata, S., Kumada, H., Iino, S., Kiyosawa, K
  • Journal Title: Hepatology Research 37(8) Pages: 661-666
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Management of HBV infection in Japan. (2007)
  • Author(s): Minami M, Okanoue T.
  • Journal Title: Hepatol Res. 37
  • NAID: 10019566326
• [Journal Article] Role of cell-cycle turnover and oxidative stress in telomere shortening and cellular senescence in patients with chronic hepatitis C. (2007)
  • Author(s): Sekoguchi S, et. al.
  • Journal Title: J Gastroenterol Hepatol. 22(2) Pages: 182-90
  • Peer Reviewed
• [Journal Article] Low serum level of hepatitis B core-related antigen indicates unlikely reactivation of hepatitis after cessation of lamivudine therapy. (2007)
  • Author(s): Matsumoto A, et. al.
  • Journal Title: Hepatol Res. 37(8) Pages: 661-6
  • Peer Reviewed
• [Journal Article] Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance (2006)
  • Author(s): Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, Okanoue T, Minami M, Chayama K, Imamura M, Yatsuhashi H, Nagaoka S, Ybtsuyanagi H, Kawata S, Kimura T, Maki N, Iino S, Kiyosawa K; HBV Core-Related Antigen Study Group
  • Journal Title: Liver International 26(1) Pages: 90-96
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Update of research and management of hepatitis B (2006)
  • Author(s): Okanoue T, Minami M.
  • Journal Title: Journal of Gastroenterology 41(2) Pages: 107-118
  • NAID: 10017420911
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Prediction of breakthrough hepatitis due to lamivudine-resistant hepatitis B virus by a sensitive semiquantitative assay using peptide nucleic acids (2006)
  • Author(s): Mori K, Minami M, Kirishima T, Kunimoto K, Okita M, Nakayama M, Makiyama A, Yamaoka J, Nakajima T, Yasui K, Itoh Y, Okanoue T.
  • Journal Title: Intervirology 49(5) Pages: 274-280
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Umusually high incidence of hepatitis B virus integration into the MLL gene in hepatocellular carcinoma (2006)
  • Author(s): Minami M, Fujii K, Miyagawa M, Okanoue T.
  • Journal Title: Clinical Cancer Research 12(11Pt1) Pages: 3549-3550
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] HBV Core-Related Antigen Study Group. Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance (2006)
  • Author(s): Tanaka, E, Matsumoto, A, Suzuki, F, Kobayashi, M, Mizokami, M, Tanaka, Y, Okanoue, T, Minami, M, Chayama, K, Imamura, M, Yatsuhashi, H, Nagaoka, S, Yotsuyanagi, H, Kawata, S, Kimura, T, Maki, N, Iino, S, Kiyosawa, K
  • Journal Title: Liver International 26(1) Pages: 90-96
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Update of research and management of hepatitis B (2006)
  • Author(s): Okanoue, T., Minami, M
  • Journal Title: Journal of Gastroenterology 41(2) Pages: 107-118
  • NAID: 10017420911
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prediction of breakthrough hepatitis due to lamivudine-resistant hepatitis B virus by a sensitive semiquantitative assay using peptide nucleic acids (2006)
  • Author(s): Mori, K., Minami, M., Kirishima, T., Kunimoto, K., Okita, M., Nakayama, M., Makiyama, A., Yamaoka, J., Nakajima, T., Yasui, K., Itoh, Y., Okanoue, T
  • Journal Title: Intervirology 49(5) Pages: 274-280
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unusually high incidence of hepatitis B virus integration into the MLL gene in hepatocellular carcinoma (2006)
  • Author(s): Minami, M., Fujii, K., Miyagawa, M., Okanoue, T
  • Journal Title: Clinical Cancer Research 12(11 Pt 1) Pages: 3549-3550
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Unusually high incidence of hepatitis B virus integration into the MLL gene in hepatocellular carcinoma. (2006)
  • Author(s): Minami M, Fujii K, Miyagawa M, Okanoue T
  • Journal Title: Clinical Cancer Research 12 Pages: 3549-3549
• [Journal Article] Prediction of breakthrough hepatitis due to lamivudine-resistant hepatitis B virus by a sensitive semiquantitative assay using peptide nucleic acides. (2006)
  • Author(s): Mori K, Minami M, Kirishima T, Kunimoto K, Okita M, Nakayama M, Makiyama A, Yamaoka J, Nakajima T, Yasui K, Itoh Y, Okanoue T
  • Journal Title: Intervirology 49・5 Pages: 274-280
• [Journal Article] Update of research and management of hepatitis B. (2006)
  • Author(s): Okanoue T, Minami M
  • Journal Title: Update of research and management of hepatitis B. 41・2 Pages: 107-118
  • NAID: 10017420911
• [Journal Article] Measurement of hepatitis B virus core-related antigen is valuable for identifying patients who are at low risk of lamivudine resistance. (2006)
  • Author(s): Tanaka E, Matsumoto A, Suzuki F, Kobayashi M, Mizokami M, Tanaka Y, Okanoue T, Minami M, Chayama K, Imamura M, Yatsuhashi H, Nagaoka S, Yotsuyanagi H, Kawata S, Kimura T, Maki N, Iino S, Kiyosawa K
  • Journal Title: Liver International 26・1 Pages: 90-96
• [Presentation] Lamivudine with sequential interferon therapy in Japanese patients with chronic hepatitis type B. (2007)
  • Author(s): Minami M, et. al.
  • Organizer: 15th Asian Pacific Association for the Study of the Liver Conference.
  • Place of Presentation: 京都
  • Year and Date: 2007-05-28
• [Presentation] Lamivudine with sequential interferon therapy in Japanese patients with chronic hepatitis type B (2007)
  • Author(s): Minami M, Mori K, Fujii K, Miyagawa M, Itoh Y, Okanoue T.
  • Organizer: 15th Asian Pacific Association for the Study of the Liver Conference
  • Place of Presentation: Kyoto
  • Year and Date: 2007-03-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] HBV reactivation with altered HBs antigenicity in a patient who received rituximab (2007)
  • Author(s): Miyagawa M, Minami M, Hashimoto H, Sendo R, Fujii K, Ito Y, Shimizu D, Matsumoto Y, Taniwaki M, Okanoue T.
  • Organizer: 15th Asian Pacific Association for the Study of the Liver Conference
  • Place of Presentation: Kyoto
  • Year and Date: 2007-03-28
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 長期寛解を目指したラミブジン・インターフェロン併用療法. パネルディスカッション1;コンセンサスミーティング・B型肝炎の治療 (2006)
  • Author(s): 南 祐仁, 岡上 武
  • Organizer: 第48回日本消化器病学会大会, 第10回日本肝臓学会大会(DDW-Japan2006)
  • Place of Presentation: 札幌
  • Year and Date: 2006-10-11
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Management of HBV infection in Japan (2006)
  • Author(s): Minami M, Okanoue T.
  • Organizer: International Symposium on HBV
  • Place of Presentation: Kyoto
  • Year and Date: 2006-05-27
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Management of HBV infection in Japan (2006)
  • Author(s): Minami, M., Okanoue, T
  • Organizer: International Symposium on HBV
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 2006-05-27
  • Description: 「研究成果報告書概要(欧文)」より
• [Presentation] 組み込み旺BVをタグとした肝発癌関連遺伝子の同定. ワークショップ1;ウイルス性肝炎研究の最先端 (2006)
  • Author(s): 南 祐仁, 藤井 恒太, 宮川 昌巳, 伊藤 義人, 森康 二郎, 岡上 武
  • Organizer: 第42回日本肝臓学会総会
  • Place of Presentation: 京都
  • Year and Date: 2006-05-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] 悪性リンパ腫の治療後に発症したHBs抗原陰性,HBVDNA陽性の急性肝炎 (2006)
  • Author(s): 宮川 昌巳, 南 祐仁, 橋本 宏明, 森康 二郎, 藤井 恒太, 伊藤 義人, 清水 大介, 松本 洋典, 谷脇 雅史, 岡上 武
  • Organizer: 第42回日本肝臓学会総会
  • Place of Presentation: 京都
  • Year and Date: 2006-05-25
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] HBV組み込みによるヒト遺伝子の発現修飾と肝細胞増殖. ワークショップ5;肝炎ウイルスによる肝障害機序と肝発癌機序の解明 (2006)
  • Author(s): 南 祐仁, 藤井 恒太, 岡上 武
  • Organizer: 第92回日本消化器病学会総会
  • Place of Presentation: 北九州
  • Year and Date: 2006-04-21
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Identification of cancerrelated genes using HBV integration as a sequencetag (2006)
  • Author(s): Minami M, Fujii K, Miyagawa M, Itoh Y, Okanoue T.
  • Organizer: Annual Meeting of the American Association for the Study of Liver Disease(AASLD)
  • Place of Presentation: Boston,USA
  • Description: 「研究成果報告書概要(和文)」より
• [Presentation] Identification of cancer-related genes using HBV integration as a sequence tag (2006)
  • Author(s): Minami, M., Fujii, K., Miyagawa, M., Itoh, Y., Okanoue, T
  • Organizer: Annual Meeting of the American Association for the Study of Liver Disease (AASLD)
  • Place of Presentation: Boston, USA
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 今日の診療のために ガイドライン 外来診療2007, 泉 孝英, 編 (2007)
  • Author(s): 南祐 仁
  • Publisher: 日経メディカル開発,東京
  • Description: 「研究成果報告書概要(和文)」より
• [Book] コンセンサス肝疾患B型肝炎・C型肝炎の治療.坪内博仁, 監修 (2007)
  • Author(s): 南祐 仁, 岡上 武
  • Publisher: 日本メディカルセンター,東京
  • Description: 「研究成果報告書概要(和文)」より
• [Book] 臨床に直結する肝・胆・膵疾患治療のエビデンス.跡見裕, 上村直実, 白鳥敬子, 正木尚彦, 編集 (2007)
  • Author(s): 南祐 仁, 岡上 武
  • Publisher: 文光堂,東京
  • Description: 「研究成果報告書概要(和文)」より