DNA methylation and IDH mutations in intrahepatic cholangiocarcinoma

• Project/Area Number: 20K16418
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Kumamoto University
• Principal Investigator: Miyata tatsunori 熊本大学, 生命科学研究部(医), 特定研究員 (80594887)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 肝内胆管癌 / LINE-1 / DNAメチル化 / エピジェネティクス / IDH変異 / IDH

Outline of Research at the Start

熊本大学病院におけるICCの切除サンプルを用いて、パイロシークエンス法にてLINE-1のメチル化及びIDH変異の有無について検討を行う。得られた結果を元に、LINE-1のメチル化及びIDH変異の有無と臨床病理学的背景 (年齢、性別、腫瘍マーカー、腫瘍の大きさ、リンパ節転移、脈管侵襲の有無、進行度等)及び肝切除後の予後との関連を統合的に解析する。さらに、LINE-1のメチル化レベルとIDH変異の相互の関連についても併せて評価する。この成果は、LINE-1、IDHの地位の確立と新たな治療ターゲットの発見につながり、ICCの予後予測及び予後改善に重要な意義を持つと考える。

Outline of Final Research Achievements

Methylation of LINE-1 promoter region in cancerous and noncancerous areas was measured in resected samples of intrahepatic cholangiocarcinoma (ICC). In the analysis of clinicopathologic factors and LINE-1 methylation levels, the hypomethylated group had a significantly higher frequency of lymph node metastases (p=0.04) and a significantly worse prognosis in overall survival (Log-rank p=0.045), but there was no difference between the two groups in recurrence-free survival.
IDH mutations (IDH1 and IDH2) were found in 9 of 72 patients (12.5%), including 8 patients (11.1%) with IDH1 mutation and 1 patient (1.4%) with IDH2 mutation. The relationship between clinicopathological factors and IDH mutations was evaluated in the 67 patients for whom patient information was available, and no statistically significant differences in clinicopathological factors, prognosis, or LINE-1 methylation levels were found between the two groups.

Academic Significance and Societal Importance of the Research Achievements

ICCは予後不良な肝がんの一組織型である。術後も早期に再発することから、その予後を予測し再発や予後が不良なICCを同定することは重要である。本研究により、ICCのLINE-1メチル化が低い症例はリンパ節転移が有意に多く、肝切除後の予後が悪かった。しかしながら、IDH変異との関連は示されなかった。より大きなサンプルを用いてLINE-1メチル化を用いたICCの予後予測についてさらなる検討が必要である。

Research Products

• [Journal Article] Gut microbial trimethylamine is elevated in alcohol-associated hepatitis and contributes to ethanol-induced liver injury in mice (2022)
  • Author(s): Helsley RN, Miyata T, Kadam A, Nagy LE, Brown JM et al.
  • Journal Title: eLife Volume: 11
  • DOI: 10.7554/elife.76554
  • Peer Reviewed / Open Access
• [Journal Article] Nontumor related risk score: A new tool to improve prediction of prognosis after hepatectomy for colorectal liver metastases (2022)
  • Author(s): Sasaki K, Margonis GA, Miyata T, Pawlik TM et al.
  • Journal Title: Surgery Volume: - Issue: 6 Pages: 1580-1587
  • DOI: 10.1016/j.surg.2022.01.030
  • Peer Reviewed
• [Journal Article] Efficacy of a newly developed bioabsorbable pancreatic clip for distal pancreatectomy in swine (2022)
  • Author(s): Yamashita Yo-ichi、Yamao Takanobu、Nakao Yosuke、Miyata Tatsunori、Ikegami Yasuhiro、Yamane Soichiro、Ito Taiga、Furukawa Taku、Cho Jaeyong、Wu Fanqi、Fujie Yasumitsu、Arima Mitsuru、Aishima Shinichi、Ijima Hiroyuki、Baba Hideo
  • Journal Title: Surgery Today Volume: - Issue: 7 Pages: 1109-1114
  • DOI: 10.1007/s00595-021-02435-x
  • Peer Reviewed
• [Journal Article] Efficacy of Ring Drape and Unused Sterile Instruments for Incisional SSI After Hepatectomy (2022)
  • Author(s): YUSA TOSHIHIKO、YAMASHITA YO-ICHI、NITTA HIDETOSHI、NAKAO YOSUKE、ITOYAMA RUMI、KITANO YUKI、KAIDA TAKAYOSHI、MIYATA TATSUNORI、MIMA KOSUKE、IMAI KATSUNORI、HAYASHI HIROMITSU、BABA HIDEO
  • Journal Title: Anticancer Research Volume: 42 Issue: 2 Pages: 1007-1012
  • DOI: 10.21873/anticanres.15561
  • Peer Reviewed
• [Journal Article] Alcohol Consumption Is Associated with Poor Prognosis in Obese Patients with COVID-19: A Mendelian Randomization Study Using UK Biobank (2021)
  • Author(s): Fan Xiude、Liu Zhengwen、Poulsen Kyle L.、Wu Xiaoqin、Miyata Tatsunori、Dasarathy Srinivasan、Rotroff Daniel M.、Nagy Laura E.
  • Journal Title: Nutrients Volume: 13 Issue: 5 Pages: 1592-1592
  • DOI: 10.3390/nu13051592
  • Peer Reviewed / Open Access
• [Journal Article] Identification of a MicroRNA‐E3 Ubiquitin Ligase Regulatory Network for Hepatocyte Death in Alcohol‐Associated Hepatitis (2021)
  • Author(s): Fan Xiude、Wu Jianguo、Poulsen Kyle L.、Kim Adam、Wu Xiaoqin、Huang Emily、Miyata Tatsunori、Sanz‐Garcia Carlos、Nagy Laura E.
  • Journal Title: Hepatology Communications Volume: 5 Issue: 5 Pages: 830-845
  • DOI: 10.1002/hep4.1677
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in precision medicine for pancreatic ductal adenocarcinoma (2021)
  • Author(s): Hayashi Hiromitsu、Higashi Takaaki、Miyata Tatsunori、Yamashita Yo‐ichi、Baba Hideo
  • Journal Title: Annals of Gastroenterological Surgery Volume: 5 Issue: 4 Pages: 457-466
  • DOI: 10.1002/ags3.12436
  • Peer Reviewed / Open Access
• [Journal Article] Metabolic shift to serine biosynthesis through 3-PG accumulation and PHGDH induction promotes tumor growth in pancreatic cancer (2021)
  • Author(s): Itoyama R, Yasuda-Yoshihara N, Kitamura F, Yasuda T, Bu L, Yonemura A, Uchihara T, Arima K, Hu X, Jun Z, Okamoto Y, Akiyama T, Yamashita K, Nakao Y, Yusa T, Kitano Y, Higashi T, Miyata T, Imai K, Hayashi H, Yamashita Y, Mikawa T, Kondoh H, Baba H, Ishimoto T
  • Journal Title: Cancer Letters Volume: 523 Pages: 29-42
  • DOI: 10.1016/j.canlet.2021.09.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Impact of Histologic Liver Inflammation on Oncology and the Prognosis of Patients Undergoing Hepatectomy for Hepatocellular Carcinoma (2021)
  • Author(s): Miyata Tatsunori、Hayashi Hiromitsu、Yamashita Yo-ichi、Matsumura Kazuki、Higashi Takaaki、Imai Katsunori、Nitta Hidetoshi、Chikamoto Akira、Beppu Toru、Baba Hideo
  • Journal Title: Annals of Surgical Oncology Volume: 29 Issue: 2 Pages: 893-902
  • DOI: 10.1245/s10434-021-10706-7
  • Peer Reviewed
• [Journal Article] Alteration of prognostic efficacy of albumin‐bilirubin grade and Child‐Pugh score according to liver fibrosis in hepatocellular carcinoma patients with Child‐Pugh A following hepatectomy (2021)
  • Author(s): Miyata Tatsunori、Yamashita Yo‐ichi、Arima Kota、Higashi Takaaki、Hayashi Hiromitsu、Imai Katsunori、Nitta Hidetoshi、Chikamoto Akira、Beppu Toru、Baba Hideo
  • Journal Title: Annals of Gastroenterological Surgery Volume: 6 Issue: 1 Pages: 127-134
  • DOI: 10.1002/ags3.12498
  • Peer Reviewed / Open Access
• [Journal Article] Conversion Surgery for Hepatocellular Carcinoma Following Molecular Therapy (2021)
  • Author(s): YAMAMURA KENSUKE、BEPPU TORU、MIYATA TATSUNORI、OKABE HIROHISA、NITTA HIDETOSHI、IMAI KATSUNORI、HAYASHI HIROMITSU、AKAHOSHI SHINICHI
  • Journal Title: Anticancer Research Volume: 42 Issue: 1 Pages: 35-44
  • DOI: 10.21873/anticanres.15454
  • Peer Reviewed
• [Journal Article] Differential role of MLKL in alcohol-associated and non?alcohol-associated fatty liver diseases in mice and humans (2021)
  • Author(s): Miyata T, Wu X, Fan X, Huang E, Sanz-Garcia C, Ross CKC, Roychowdhury S, Bellar A, McMullen MR, Dasarathy J, Allende DS, Caballeria J, Sancho-Bru P, McClain CJ, Mitchell M, McCullough AJ, Radaeva S, Barton B, Szabo G, Dasarathy S, Nagy LE
  • Journal Title: JCI Insight Volume: 6 Issue: 4
  • DOI: 10.1172/jci.insight.140180
  • Peer Reviewed / Open Access
• [Journal Article] High ARHGEF2 (GEF-H1) Expression is Associated with Poor Prognosis Via Cell Cycle Regulation in Patients with Pancreatic Cancer (2021)
  • Author(s): Nakao Yosuke、Nakagawa Shigeki、Yamashita Yo-ichi、Umezaki Naoki、Okamoto Yuya、Ogata Yoko、Yasuda-Yoshihara Noriko、Itoyama Rumi、Yusa Toshihiko、Yamashita Kohei、Miyata Tatsunori、Okabe Hirohisa、Hayashi Hiromitsu、Imai Katsunori、Baba Hideo
  • Journal Title: Annals of Surgical Oncology Volume: － Issue: 8 Pages: 4733-4743
  • DOI: 10.1245/s10434-020-09383-9
  • Peer Reviewed
• [Journal Article] Effect of Acid Suppressants on the Risk of COVID-19: A Propensity Score-Matched Study Using UK Biobank (2021)
  • Author(s): Fan Xiude、Liu Zhengwen、Miyata Tatsunori、Dasarathy Srinivasan、Rotroff Daniel M.、Wu Xiaoqin、Poulsen Kyle L.、Nagy Laura E.
  • Journal Title: Gastroenterology Volume: 160 Issue: 1 Pages: 455-458.e5
  • DOI: 10.1053/j.gastro.2020.09.028
  • Peer Reviewed
• [Journal Article] Programmed cell death in alcohol-associated liver disease (2020)
  • Author(s): Miyata Tatsunori、Nagy Laura E.
  • Journal Title: Clinical and Molecular Hepatology Volume: 26 Issue: 4 Pages: 618-625
  • DOI: 10.3350/cmh.2020.0142
  • Peer Reviewed / Open Access
• [Journal Article] ASO Author Reflections: Prognostic Value of the Preoperative Tumor Marker Index in Resected Pancreatic Ductal Adenocarcinoma: A Retrospective Single Institutional Study (2020)
  • Author(s): Miyata Tatsunori、Hayashi Hiromitsu、Baba Hideo
  • Journal Title: Annals of Surgical Oncology Volume: 27 Issue: S3 Pages: 903-904
  • DOI: 10.1245/s10434-020-09039-8
  • Peer Reviewed
• [Journal Article] Prognostic Value of the Preoperative Tumor Marker Index in Resected Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Institution Study (2020)
  • Author(s): Miyata Tatsunori、Hayashi Hiromitsu、Yamashita Yo-ichi、Matsumura Kazuki、Nakao Yosuke、Itoyama Rumi、Yamao Takanobu、Tsukamoto Masayo、Okabe Hirohisa、Imai Katsunori、Chikamoto Akira、Ishiko Takatoshi、Baba Hideo
  • Journal Title: Annals of Surgical Oncology Volume: 28 Issue: 3 Pages: 1572-1580
  • DOI: 10.1245/s10434-020-09022-3
  • Peer Reviewed
• [Journal Article] 12-chemokine signature, a predictor of tumor recurrence in colorectal cancer (2020)
  • Author(s): Tokunaga Ryuma、Nakagawa Shigeki、Sakamoto Yasuo、Nakamura Kenichi、Naseem Madiha、Izumi Daisuke、Kosumi Keisuke、Taki Katsunobu、Higashi Takaaki、Miyata Tatsunori、Miyamoto Yuji、Yoshida Naoya、Baba Hideo、Lenz Heinz-Josef
  • Journal Title: International Journal of Cancer Volume: 147(2) Issue: 2 Pages: 532-541
  • DOI: 10.1002/ijc.32982
  • Peer Reviewed