Therapeutic targetable fusion genes in ovarian carcinoma

• Project/Area Number: 16H06267
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Obstetrics and gynecology
• Research Institution: Niigata University
• Principal Investigator: Yoshihara Kosuke 新潟大学, 医歯学系, 研究准教授 (40547535)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥23,140,000 (Direct Cost: ¥17,800,000、Indirect Cost: ¥5,340,000); Fiscal Year 2018: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000); Fiscal Year 2017: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000); Fiscal Year 2016: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: 融合遺伝子 / トランスレーショナルリサーチ / ゲノム医学 / 卵巣癌 / 腫瘍免疫

Outline of Final Research Achievements

The frequency and function of fusion genes in ovarian cancer remained unclear. Our aim of this study was to identify fusion genes in ovarian cancer through RNA sequencing data analysis and to clarify clinical significance of fusion genes in ovarian cancer. We performed RNA sequencing for 57 ovarian clear cell carcinoma samples and detected fusion genes based on our PRADA algorithm. Of 57 samples, ten harbored at least one therapeutically targetable fusion gene such as kinase fusion genes. In addition, 18 samples had at least one fusion gene which might be recognized as a neoantigen by host. In conclusion, gene fusion was one of important genomic alterations in clinical field as well as tumorigenesis.

Academic Significance and Societal Importance of the Research Achievements

卵巣明細胞癌は日本人に多い組織型で、標準的な抗がん剤が効きにくいことが知られている。本研究では、卵巣明細胞癌の融合遺伝子プロファイルを同定することによって、新たな治療標的を同定することができ、今後の分子標的薬の開発につながる可能性がある。また融合遺伝子をneoantigenとしてとらえることで、腫瘍免疫においても、免疫チェックポイント阻害薬の有望な分子マーカーになり、高額な免疫チェックポイント阻害薬による治療対象を最適化することができる可能性があり、医療経済的にも重要な研究成果と言える。

Research Products

• [Journal Article] Concurrent isolated retroperitoneal HGSC and STIC defined by somatic mutation analysis: a case report (2019)
  • Author(s): Suda Kazuaki、Nakaoka Hirofumi、Hata Chihiro、Yahata Natsumi、Isobe Masanori、Kameyama Hitoshi、Wakai Toshifumi、Motoyama Teiichi、Inoue Ituro、Yoshihara Kosuke、Enomoto Takayuki
  • Journal Title: Diagnostic Pathology Volume: 14 Issue: 1 Pages: 17-17
  • DOI: 10.1186/s13000-019-0795-3
  • Peer Reviewed / Open Access
• [Journal Article] Novel MXD4-NUTM1 fusion transcript identified in primary ovarian undifferentiated small round cell sarcoma (2018)
  • Author(s): Tamura Ryo、Nakaoka Hirofumi、Yoshihara Kosuke、Mori Yutaro、Yachida Nozomi、Nishikawa Nobumichi、Motoyama Teiichi、Okuda Shujiro、Inoue Ituro、Enomoto Takayuki
  • Journal Title: Genes, Chromosomes and Cancer Volume: 57 Issue: 11 Pages: 557-563
  • DOI: 10.1002/gcc.22668
  • Peer Reviewed / Open Access
• [Journal Article] Clonal Expansion and Diversification of Cancer-Associated Mutations in Endometriosis and Normal Endometrium (2018)
  • Author(s): Suda Kazuaki、Nakaoka Hirofumi、Yoshihara Kosuke、Ishiguro Tatsuya、Tamura Ryo、Mori Yutaro、Yamawaki Kaoru、Adachi Sosuke、Takahashi Tomoko、Kase Hiroaki、Tanaka Kenichi、Yamamoto Tadashi、Motoyama Teiichi、Inoue Ituro、Enomoto Takayuki
  • Journal Title: Cell Reports Volume: 24 Issue: 7 Pages: 1777-1789
  • DOI: 10.1016/j.celrep.2018.07.037
  • Peer Reviewed / Open Access
• [Journal Article] The Safety and Effectiveness of Abdominal Radical Trachelectomy for Early-Stage Cervical Cancer During Pregnancy (2018)
  • Author(s): Yoshihara Kosuke、Ishiguro Tatsuya、Chihara Makoto、Shima Eiri、Adachi Sosuke、Isobe Masanori、Haino Kazufumi、Yamaguchi Masayuki、Sekine Masayuki、Kashima Katsunori、Takakuwa Koichi、Nishikawa Nobumichi、Enomoto Takayuki
  • Journal Title: International Journal of Gynecologic Cancer Volume: 28 Issue: 4 Pages: 782-787
  • DOI: 10.1097/igc.0000000000001218
• [Journal Article] Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions (2018)
  • Author(s): Tamura R, Yoshihara K, Saito T, Ishimura R, Martinez-Ledesma JE, Xin H, Ishiguro T, Mori Y, Yamawaki K, Suda K, Sato S, Itamochi H, Motoyama T, Aoki Y, Okuda S, Casingal CR, Nakaoka H, Inoue I, Verhaak RGW, Komatsu M, Enomoto T.
  • Journal Title: Oncogenesis Volume: 7 Issue: 1 Pages: 4-4
  • DOI: 10.1038/s41389-017-0018-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The impact of stromal Hic-5 on the tumorigenesis of colorectal cancer through lysyl oxidase induction and stromal remodeling. (2018)
  • Author(s): Omoto T, Kim-Kaneyama JR, Lei XF, Orimo A, Ohnishi K, Yoshihara K, Miyauchi A, Li S, Gao L, Umemoto T, Tanaka J, Nakahara K, Takeya M, Ishida F, Kudo SE, Haraguchi S, Miyazaki T, Miyazaki A.
  • Journal Title: Oncogene. Volume: 37 Issue: 9 Pages: 1205-1219
  • DOI: 10.1038/s41388-017-0033-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] TumorFusions: an integrative resource for cancer-associated transcript fusions (2018)
  • Author(s): Hu Xin、Wang Qianghu、Tang Ming、Barthel Floris、Amin Samirkumar、Yoshihara Kosuke、Lang Frederick M、Martinez-Ledesma Emmanuel、Lee Soo Hyun、Zheng Siyuan、Verhaak Roel G W
  • Journal Title: Nucleic Acids Research Volume: 46 Issue: D1 Pages: D1144-D1149
  • DOI: 10.1093/nar/gkx1018
• [Journal Article] In vivo loss-of-function screens identify KPNB1 as a new druggable oncogene in epithelial ovarian cancer (2017)
  • Author(s): Kodama Michiko、Kodama Takahiro、Newberg Justin Y.、Katayama Hiroyuki、Kobayashi Makoto、Hanash Samir M.、Yoshihara Kosuke、Wei Zhubo、Tien Jean C.、Rangel Roberto、Hashimoto Kae、Mabuchi Seiji、Sawada Kenjiro、Kimura Tadashi、Copeland Neal G.、Jenkins Nancy A.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 114 Issue: 35
  • DOI: 10.1073/pnas.1705441114
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Whole-genome sequencing revealed novel prognostic biomarkers and promising targets for therapy of ovarian clear cell carcinoma. (2017)
  • Author(s): Itamochi H, Oishi T, Oumi N, Takeuchi S, Yoshihara K, Mikami M, Yaegashi N, Terao Y, Takehara K, Ushijima K, Watari H, Aoki D, Kimura T, Nakamura T, Yokoyama Y, Kigawa J, Sugiyama T.
  • Journal Title: British Journal of Cancer Volume: 117 Issue: 5 Pages: 717-724
  • DOI: 10.1038/bjc.2017.228
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism (2017)
  • Author(s): Sapkota Y, Steinthorsdottir V, Morris AP, et al.
  • Journal Title: Nature Communications Volume: 8 Issue: 1 Pages: 15539-15539
  • DOI: 10.1038/ncomms15539
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sox2-dependent inhibition of p21 is associated with poor prognosis of endometrial cancer (2017)
  • Author(s): Yamawaki K, Ishiguro T, Mori Y, Yoshihara K, Suda K, Tamura R, Yamaguchi M, Sekine M, Kashima K, Higuchi M, Fujii M, Okamoto K, Enomoto T
  • Journal Title: Cancer Sci. Volume: 108 Issue: 4 Pages: 632
  • DOI: 10.1111/cas.13196
  • Peer Reviewed / Open Access
• [Presentation] The first nationwide Japanese multicenter study: Characterizing the cross-sectional approach to ovarian cancer genetic testing of BRCA (CHARLOTTE) (2019)
  • Author(s): Kosuke Yoshihara, Takayuki Enomotoa, Daisuke Aoki, Yoh Watanabe, Junzo Kigawa, Nobuhiro Takeshima, Keita Fujikawa, Kana Hattori, Hitoshi Tsuda, Toru Sugiyama
  • Organizer: Society of Gynecologic Oncology 50th annual meeting
  • Int'l Joint Research
• [Presentation] オミックスデータ解析から婦人科悪性腫瘍の起源を探る (2019)
  • Author(s): 吉原弘祐
  • Organizer: 第71回日本産科婦人科学会学術講演会
  • Invited
• [Presentation] 遺伝子発現プロファイルに基づいた卵巣癌の予後予測モデルの構築 (2018)
  • Author(s): 吉原弘祐、榎本隆之、日本漿液性卵巣癌研究グループ
  • Organizer: 第6回婦人科がんバイオマーカー研究会
• [Presentation] Integrated analysis of genomic and transcriptomic data in ovarian clear cell carcinoma (2018)
  • Author(s): Kosuke Yoshihara
  • Organizer: 日韓台シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] 卵巣癌における相同組換え修復異常 (2018)
  • Author(s): 吉原弘祐
  • Organizer: 第135回関東連合産科婦人科学会学術集会
  • Invited
• [Presentation] 婦人科癌ゲノミクスの現状と課題 (2018)
  • Author(s): 吉原弘祐
  • Organizer: JSAWI 2018 annual symposium
  • Invited
• [Presentation] Somatic mutations on cancer-associated genes in endometriosis and normal uterine endometrium (2018)
  • Author(s): Kosuke Yoshihara
  • Organizer: International Gynecologic Cancer Society 2018
  • Int'l Joint Research / Invited
• [Presentation] Identification of novel therapeutically targetable fusion transcripts in ovarian clear cell carcinoma (2017)
  • Author(s): Kosuke Yoshihara, Yutaro Mori, Kaoru Yamawaki, Tatsuya Ishiguro, Takayuki Enomoto
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] 卵巣明細胞癌における新規治療標的融合遺伝子の網羅的探索 (2017)
  • Author(s): 吉原 弘祐、田村 亮、森 裕太郎、山脇 芳、須田 一暁、石黒 竜也、榎本 隆之
  • Organizer: 第16回日本婦人科がん分子標的研究会
• [Presentation] Synthetic lethality in ovarian cancer (2017)
  • Author(s): Kosuke Yoshihara
  • Organizer: The 5th Biennial Meeting of Asian Society of Gynecologic Oncology (ASGO 2017)
  • Int'l Joint Research / Invited
• [Presentation] The significance of activated PI3K/AKT pathway in FGFR3-TACC3 fusion positive cervical cancer (2017)
  • Author(s): Ryo Tamura
  • Organizer: American Association of Cancer Research Annual Meeting 2017
  • Place of Presentation: Washington DC, USA
  • Int'l Joint Research
• [Presentation] Identification of therapeutically targetable FGFR-fusion genes in cervical cancer through RNA sequencing (2017)
  • Author(s): Ryo Tamura
  • Organizer: 第69回日本産科婦人科学会学術講演会
  • Place of Presentation: 広島県立総合体育館（広島県広島市）
  • Int'l Joint Research