Molecular classification of biliary cancer by transcriptome analysis of FFPE specimens

• Project/Area Number: 18K07956
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: Arai Yasuhito 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (80222727)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 胆道がん / 分子標的 / 分子診断 / トランスクリプトーム / トランスクリプトーム解析 / FGFR2

Outline of Final Research Achievements

Biliary tract cancer (BTC) is an intractable tumor with poor prognosis, whose incidence and mortality rates are high in East Asia and have been rapidly increasing worldwide. FGFR2 rearrangement is expected to be a novel therapeutic target in advanced/recurrent BTC. Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH) and RNA sequencing. A total of 445 patients were enrolled (PRELUDE study). Twenty-three patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive. Younger age (<65 years), and HCV/HBV-positivity were significantly associated with the presence of FGFR2 rearrangement.

Academic Significance and Societal Importance of the Research Achievements

胆道がんは、日本を始めアジアでの発症が比較的多いものの予後不良な難治性の稀少がんであり、新たな治療法の開発が望まれている。我々は以前の研究によって胆道がんの新しい分子標的治療対象としてFGFR2融合遺伝子を同定している。本研究では、日常診療での生検FFPE検体を用いてFGFR2遺伝子の再構成をFISHとNGS解析による分子診断系を確立した。445名の進行/再発の日本人胆道がん患者を対象にした前向きスクリーニングを行い、FGFR2遺伝子再構成を同定して臨床試験に繋げることができた。

Research Products

• [Journal Article] Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study) (2021)
  • Author(s): Maruki Y, Morizane C, Arai Y, Ikeda M, Ueno M, Ioka T, Naganuma A, FurukawaM, Mizuno N, Uwagawa T, Takahara N, Kanai M, Asagi A, Shimizu S, Miyamoto A, Yukisawa S, Kadokura M, Kojima Y, Furuse J, Eguchi-Nakajima T, Sudo K, Kobayashi N, Hama N, Yamanaka T, Shibata T and Okusaka T.
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 3 Pages: 250-250
  • DOI: 10.1007/s00535-020-01735-2
  • Peer Reviewed / Open Access
• [Journal Article] The potential application of PD-1 blockade therapy for early-stage biliary tract cancer. (2020)
  • Author(s): Umemoto K, Togashi Y, Arai Y, Nakamura H, Takahashi S, Tanegashima T, Kato M, Nishikawa T, Sugiyama D, Kojima M, Gotohda N, Kuwata T, Ikeda M, Shibata T, Nishikawa H.
  • Journal Title: Int Immunol. Volume: 32 Issue: 4 Pages: 273-281
  • DOI: 10.1093/intimm/dxz080
  • Peer Reviewed / Open Access
• [Journal Article] E74-Like Factor 3 Is a Key Regulator of Epithelial Integrity and Immune Response Genes in Biliary Tract Cancer (2020)
  • Author(s): Suzuki Masami、Saito-Adachi Mihoko、Arai Yasuhito、Fujiwara Yuko、Takai Erina、Shibata Shinsuke、Seki Masahide、Rokutan Hirofumi、Maeda Daichi、Horie Masafumi、Suzuki Yutaka、Shibata Tatsuhiro、Kiyono Tohru、Yachida Shinichi
  • Journal Title: Cancer Research Volume: 81 Issue: 2 Pages: 489-500
  • DOI: 10.1158/0008-5472.can-19-2988
  • Peer Reviewed / Open Access
• [Journal Article] Expanding the clinicopathologic and molecular spectrum of BCOR-associated sarcomas in adults. (2020)
  • Author(s): Yoshida A, Arai Y, Hama N, Chikuta H, Bando Y, Nakano S, Kobayashi E, Shibahara J, Fukuhara H, Komiyama M, Watanabe SI, Tamura K, Kawai A, Shibata T.
  • Journal Title: Histopathology Volume: 76 Issue: 4 Pages: 509-520
  • DOI: 10.1111/his.14023
  • Peer Reviewed / Open Access
• [Journal Article] Sarcoma with MGA-NUTM1 fusion in the lung: an emerging entity. (2020)
  • Author(s): Goto T, Arai Y, Shibata T, Oyama T, Yoshida A.
  • Journal Title: Virchows Archiv Volume: 476 Issue: 2 Pages: 317-322
  • DOI: 10.1007/s00428-019-02623-8
  • Peer Reviewed
• [Journal Article] KMT2A (MLL) fusions in aggressive sarcomas in young adults. (2019)
  • Author(s): Yoshida A, Arai Y, Tanzawa Y, Wakai S, Hama N, Kawai A, Shibata T.
  • Journal Title: Histopathology Volume: 75 Issue: 4 Pages: 508-516
  • DOI: 10.1111/his.13926
  • Peer Reviewed / Open Access
• [Journal Article] A computational tool to detect DNA alterations tailored to formalin-fixed paraffin-embedded samples in cancer clinical sequencing (2018)
  • Author(s): Kato M, Nakamura H, Nagai M, Kubo T, Elzawahry A, Totoki Y, Tanabe Y, Furukawa E, Miyamoto J, Sakamoto H, Matsumoto S, Sunami K, Arai Y, Suzuki Y, Yoshida T, Tsuchihara K, Tamura K, Yamamoto N, Ichikawa H, Kohno T and Shibata T
  • Journal Title: Genome Medicine Volume: 10 Issue: 1 Pages: 44-44
  • DOI: 10.1186/s13073-018-0547-0
  • Peer Reviewed
• [Journal Article] Epigenetic landscape influences the liver cancer genome architecture (2018)
  • Author(s): Natsuko Hama, Yasushi Totoki, Fumihito Miura, Kenji Tatsuno, Mihoko Saito-Adachi, Hiromi Nakamura, Yasuhito Arai, Fumie Hosoda, Tomoko Urushidate, Shoko Ohashi, Wakako Mukai, Nobuyoshi Hiraoka, Hiroyuki Aburatani , Takashi Ito and Tatsuhiro Shibata
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 1643-1643
  • DOI: 10.1038/s41467-018-03999-y
  • Peer Reviewed / Open Access
• [Journal Article] Integrated genetic and epigenetic analysis of myxofibrosarcoma (2018)
  • Author(s): Koichi Ogura, Fumie Hosoda, Yasuhito Arai, Hiromi Nakamura, Natsuko Hama, Yasushi Totoki, Akihiko Yoshida, Momoko Nagai, Mamoru Kato, Erika Arakawa, Wakako Mukai, Hirofumi Rokutan, Akira Kawai, Sakae Tanaka and Tatsuhiro Shibata
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 2765-2765
  • DOI: 10.1038/s41467-018-03891-9
  • Peer Reviewed / Open Access
• [Presentation] Molecular genetic analysis of BCOR-rearranged sarcoma (2020)
  • Author(s): 新井康仁、 吉田朗 彦、 濱 奈津子、 知久田大史、小林英介、坂東良美、柴原純二、川井 章、柴田龍弘
  • Organizer: 日本癌学会学術総会
• [Presentation] Frequency and clinicopathological characteristics of biliary tract carcinomas harboring the FGFR2-fusion gene: a prospective observational study (PRELUDE study). (2019)
  • Author(s): M. Ikeda, Y. Maruki, M. Ueno, T. Ioka, A. Naganuma, M. Furukawa, N. Mizuno, T. Uwagawa, Y. Nakai, M. Kanai, A. Asagi, S. Shimizu, A. Miyamoto, S. Yukisawa, M. Kadokura, T. Yamanaka, Y. Arai, T. Shibata, C. Morizane, T. Okusaka.
  • Organizer: ESMO
  • Int'l Joint Research
• [Presentation] 肉腫におけるCIC遺伝子再構成の分子遺伝学的解析 (2018)
  • Author(s): 新井康仁、吉田朗彦、濱 奈津子、向 和加子、知久田大史、十時 泰、小倉浩一、小林英介、元井 亨、川井 章、平岡伸介、柴田龍弘
  • Organizer: 日本癌学会学術総会