Identification of diagnostic marker of combined hepatocellular-cholangiocarcinoma subtypes by gene expression analysis

• Project/Area Number: 18K07032
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Kurume University
• Principal Investigator: YANO Hirohisa 久留米大学, 医学部, 教授 (40220206)
• Co-Investigator(Kenkyū-buntansha): 秋葉 純 久留米大学, 大学病院, 教授 (00341305) ; 小笠原 幸子 久留米大学, 医学部, 講師 (40258405)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥130,000 (Direct Cost: ¥100,000、Indirect Cost: ¥30,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 混合型肝癌 / 中間細胞型 / 免疫染色 / 組織診断マーカー / 遺伝子発現 / 肝細胞癌 / 胆管細胞癌 / 中間細胞亜型 / 網羅的遺伝子解析 / 診断マーカー / ケラチン7 / ケラチン19 / HepPar-1 / 組織診断 / 肝ステム像 / マイクロアレイ / FFPE / 細胆管型 / 網羅的解析

Outline of Final Research Achievements

Combined hepatocellular-cholangiocarcinoma, intermediate-cell subtype (INT) is a rare liver tumor and could even be misdiagnosed by trained liver pathologists. We aimed to identify specific diagnostic markers of INT. We compared 4,7000 gene expression between HCC, iCCA, and INT by cDNA microarray and identified 91 significantly up- or down-regulated genes. Malic enzyme 1 (ME1) was most significantly up-regulated. Histologically, the positive rates of ME1 in INT, iCCA, and HCC were 77%, 28%, and 62%, respectively. After scoring immunohistochemical expressions of HepPar-1, ME1, K7, and K19, composite score can discriminate between INT and HCC or iCCA. INT could be discriminated from iCCA with high sensitivity (89%) and high specificity (88%). This can make precise pathological diagnosis of INT in many institutes.

Academic Significance and Societal Importance of the Research Achievements

混合型肝癌の一亜型である中間細胞型（INT）は比較的稀な腫瘍で一般病理医が遭遇することが少ない。また、多彩な組織像を示すことが多く、肝病理専門医でないと正確な診断をすることがしばしば困難である。肝細胞癌、肝内胆管癌、細胆管癌などの腫瘍と治療法や予後が異なることから正確な診断が必要である。本研究では、肝細胞マーカーのHepPar-1、胆管細胞のマーカーのK7とK19そしてMalic enzyme 1の免疫染色を腫瘍に対して行い、発現をスコア化することで高い感度(88.6%)、特異度(88.0%)でINTを診断するができる事を明らかにし、INTの診断の標準化に貢献できると確信している。

Research Products

• [Journal Article] Malic enzyme 1 is a potential marker of combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell type. (2019)
  • Author(s): Mihara Y, Akiba J, Ogasawara S, Kondo R, Fukushima H, Itadani H, Obara H, Kakuma T, Kusano H, Naito Y, Okuda K, Nakashima O, Yano H.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 9 Pages: 1066-1075
  • DOI: 10.1111/hepr.13365
  • Peer Reviewed
• [Presentation] Malic enzyme 1（ME1）は混合型肝癌中間細胞亜型の診断マーカーとして有用である (2019)
  • Author(s): 三原勇太郎、秋葉純、小笠原幸子、近藤礼一郎、福嶋浩人、板谷啓，草野弘宣、内藤嘉紀、中島収、矢野博久
  • Organizer: 第108回日本病理学会総会
• [Presentation] Malic Enzyme 1 is a potential marker of intermediate cell carcinoma, a subtype of combined hepatocellular-cholangiocarcinoma (2019)
  • Author(s): Hirohisa Yano and Yutaro Mihara
  • Organizer: The 10th Asia-Pacific Primary Liver Cancer Expert Meeting
  • Int'l Joint Research
• [Presentation] Malic Enzyme 1 is a potential marker of intermediate cell carcinoma, a subtype of combined hepatocellular-cholangiocarcinoma (2019)
  • Author(s): Hirohisa Yano
  • Organizer: 2019 Annual Meeting of Laennec Liver Pathology Society
  • Int'l Joint Research
• [Presentation] Malic enzyme 1（ME1）は混合型肝癌中間細胞亜型の診断マーカーとして有用である (2019)
  • Author(s): 三原勇太郎、秋葉純、小笠原幸子、近藤礼一郎、福嶋浩人板谷啓、草野弘宣、内藤嘉紀、中島収、矢野博久
  • Organizer: 第108回日本病理学会総会
• [Presentation] Malic enzyme 1 is a potential marker of combined hepatocellular-cholangiocarcinoma, subtypes with stem-cell features, intermediate-cell type (2019)
  • Author(s): Hirohisa Yano, Yutaro Mihara, Jun Akiba, Sachiko Ogasawara
  • Organizer: 2019 Annual Meeting of Laennec Liver Pathology Society
  • Int'l Joint Research