Exploratory research of driver gene mutation and drug sensitivity-related genes expression changes in hepatocellular carcinoma

• Project/Area Number: 17K10675
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Wakayama Medical University
• Principal Investigator: UENO Masaki 和歌山県立医科大学, 医学部, 講師 (90405465)
• Co-Investigator(Kenkyū-buntansha): 速水 晋也 和歌山県立医科大学, 医学部, 講師 (00468290) ; 川井 学 和歌山県立医科大学, 医学部, 准教授 (40398459) ; 山上 裕機 和歌山県立医科大学, 医学部, 教授 (20191190)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 腫瘍微小環境 / 肝細胞癌 / 免疫チェックポイント阻害剤 / 原発性肝癌 / 分子標的治療剤 / ゲノム / 癌 / 抗癌剤

Outline of Final Research Achievements

There was no significant association between the mutations in the driver genes and expressions in drug sensitivity-related genes. Furthermore, there was no significant relation between expressions of these drug sensitivity-related genes and the therapeutic effects of TACE therapy or molecular-targeted therapies.
Regarding the therapeutic effect in some patients received molecular-targeted therapies, there was a suggestive relation between the degree of infiltration of CD8-positive T cells around the tumor and the therapeutic effect. Therefore, not only gene expression of drug sensitivity-related genes, it was suggested that the condition of the tumor microenvironment strongly affects the therapeutic effect.

Academic Significance and Societal Importance of the Research Achievements

実臨床において薬剤治療効果を推測するには、腫瘍自体の遺伝子変異や、薬物感受性関連遺伝子の発現多寡のみならず、腫瘍微小環境の状態（抗腫瘍免疫の状態や、癌関連線維芽細胞の動態）などの解析を加える必要があることが分かった。

Research Products

• [Journal Article] Prognostic impact of adjuvant chemolipiodolization and treatment frequency on patients with hepatocellular carcinoma after hepatectomy: Prospective study with historical control group (2021)
  • Author(s): Masaki Ueno, Shinya Hayami, Manabu Kawai, Seiko Hirono, Ken-Ichi Okada, Motoki Miyazawa, Yuji Kitahata, Atsushi Miyamoto, Norihiko Suzaki, Masashi Nakamura, Hiroki Yamaue
  • Journal Title: Surg Oncol. Volume: 36 Pages: 99-105
  • DOI: 10.1016/j.suronc.2020.12.002
  • Peer Reviewed
• [Journal Article] Effective Response of Intrahepatic Cholangiocarcinoma to Pembrolizumab: A Case Report (2020)
  • Author(s): Masashi Nakamura, Masaki Ueno, Shinya Hayami, Manabu Kawai, Atsushi Miyamoto, Norihiko Suzaki, Seiko Hirono, Ken-Ichi Okada, Motoki Miyazawa, Yuji Kitahata, Ryohei Kobayashi, Fumiyoshi Kojima, Hiroki Yamaue
  • Journal Title: Anticancer Res. Volume: 40 Issue: 7 Pages: 4123-4129
  • DOI: 10.21873/anticanres.14411
  • Peer Reviewed
• [Journal Article] Prognostic Analysis of Hepatocellular Carcinoma With Hepatitis C Virus Infection Using Epithelial-Mesenchymal Transition Gene Profiles. (2020)
  • Author(s): Ueno M, Kawai M, Park JY, Hirono S, Okada KI, Hayami S, Wang HJ, Yamaue H.
  • Journal Title: J Surg Res. Volume: 245 Pages: 302-308
  • DOI: 10.1016/j.jss.2019.07.077
  • Peer Reviewed
• [Journal Article] Classification of primary liver cancer with immunosuppression mechanisms and correlation with genomic alterations. (2020)
  • Author(s): Fujita M, Yamaguchi R, Hasegawa T, Shimada S, Arihiro K, Hayashi S, Maejima K, Nakano K, Fujimoto A, Ono A, Aikata H, Ueno M, Hayami S, Tanaka H, Miyano S, Yamaue H, Chayama K, Kakimi K, Tanaka S, Imoto S, Nakagawa H.
  • Journal Title: EBioMedicine Volume: 53 Pages: 102659-102659
  • DOI: 10.1016/j.ebiom.2020.102659
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Low lymphocyte monocyte ratio after neoadjuvant therapy predicts poor survival after pancreatectomy in patients with borderline resectable pancreatic cancer. (2019)
  • Author(s): Kawai M, Hirono S, Okada KI, Miyazawa M, Shimizu A, Kitahata Y, Kobayashi R, Ueno M, Hayami S, Tanioka K, Yamaue H.
  • Journal Title: Surgery Volume: 165 Issue: 6 Pages: 1151-1160
  • DOI: 10.1016/j.surg.2018.12.015
  • Peer Reviewed
• [Journal Article] Genomic Characterization of Biliary Tract Cancers Identifies Driver Genes and Predisposing Mutations (2018)
  • Author(s): Wardell CP, Fujita M, Yamada T, Simbolo M, Fassan M, Karlic R, Polak P, Kim J, Hatanaka Y, Maejima K, Lawlor RT, Nakanishi Y, Mitsuhashi T et al
  • Journal Title: J Hepatol Volume: - Issue: 5 Pages: 959-969
  • DOI: 10.1016/j.jhep.2018.01.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma. (2018)
  • Author(s): Shigekawa Y, Hayami S, Ueno M, Miyamoto A, Suzaki N, Kawai M, Hirono S, Okada KI, Hamamoto R, Yamaue H.
  • Journal Title: Oncotarget Volume: 9 Issue: 76 Pages: 34320-34335
  • DOI: 10.18632/oncotarget.26144
  • Peer Reviewed / Open Access
• [Journal Article] Indocyanine green fluorescence imaging techniques and interventional radiology during laparoscopic anatomical liver resection (with video) (2017)
  • Author(s): Ueno Masaki、Hayami Shinya、Sonomura Tetsuo、Tanaka Ryota、Kawai Manabu、Hirono Seiko、Okada Ken-ichi、Yamaue Hiroki
  • Journal Title: Surgical Endoscopy Volume: 32 Issue: 2 Pages: 1051-1055
  • DOI: 10.1007/s00464-017-5997-8
  • Peer Reviewed
• [Journal Article] Partial clamping of the infrahepatic inferior vena cava for blood loss reduction during anatomic liver resection: A prospective, randomized, controlled trial. (2017)
  • Author(s): Ueno M, Kawai M, Hayami S, Hirono S, Okada KI, Uchiyama K, Yamaue H.
  • Journal Title: Surgery. Volume: in press Issue: 6 Pages: 1502-1513
  • DOI: 10.1016/j.surg.2016.12.010
  • Peer Reviewed
• [Journal Article] Whole genome sequencing discriminates hepatocellular carcinoma with intrahepatic metastasis from multi-centric tumors (2017)
  • Author(s): Furuta M, Ueno M, Fujimoto A, Hayami S, Yasukawa S, Kojima F, Arihiro K, Kawakami Y, Wardell CP, Shiraishi Y, Tanaka H, Nakano K, Maejima K, Sasaki-Oku A, Tokunaga N, Boroevich KA, Abe T, Aikata H, Ohdan H, Gotoh K, Kubo M, Tsunoda T, Miyano S, Chayama K, Yamaue H, Nakagawa H
  • Journal Title: J Hepatol Volume: 66(2) Issue: 2 Pages: 363-373
  • DOI: 10.1016/j.jhep.2016.09.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] A case of rapidly increased β-catenin activated hepatocellular carcinoma (2021)
  • Author(s): Hirotaka Kato, Masaki Ueno, et al.
  • Organizer: 第32回日本肝胆膵外科学会・学術集会
• [Presentation] PD-L1高発現の肝内胆管癌に対してペンブロリズマブが奏功した1例 (2020)
  • Author(s): 中村匡視、上野昌樹、他
  • Organizer: 第56回日本肝癌研究会
• [Presentation] 上皮間葉転換（EMT）関連遺伝子プロファイルを用いたC型肝炎由来肝細胞癌の 予後予測の可能性 (2019)
  • Author(s): 上野 昌樹
  • Organizer: 第55回日本肝癌研究会