Genetic characterization of unclassifiable non-small round cell sarcomas

• Project/Area Number: 18K15108
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: National Cancer Center Japan
• Principal Investigator: YOSHIDA AKIHIKO 国立研究開発法人国立がん研究センター, 中央病院, 医員 (80574780)
• 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: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肉腫 / 分類 / 病理診断 / 遺伝子変異 / 融合遺伝子 / 免疫組織化学 / 分類不能 / 分類不能肉腫

Outline of Final Research Achievements

A small subset of bone and soft tissue tumors remain diagnostically challenging. We applied next-generation sequencing to these tumors and identified novel or emerging entities/subtypes, each of which is characterized by distinct phenotype and molecular genetics, including novel NTRK3 fusions, novel KMT2A fusions, EWSR1/FUS-CREB fusion, and RREB1-MRTFB fusion. We also defined clinically relevant novel tumor subsets, including H3K27me3-deficient dedifferentiated chondrosarcoma, malignant giant cell tumor of bone lacking H3F3A mutation, and BCOR-associated sarcoma in adults. Further, we discovered diagnostically useful findings in existing entities, such as FOS fusions/upregulation in proliferative fasciitis/myositis, an effective risk stratification model for epithelioid hemangioendothelioma, and frequent NKX3.1 overexpression in mesenchymal chondrosarcoma. These achievements have contributed significantly to the classification and accurate diagnosis of bone and soft tissue tumors.

Academic Significance and Societal Importance of the Research Achievements

この研究によって、骨軟部に発生する分類困難な腫瘍のなかに、これまで知られていなかった新しい疾患単位や亜型を提唱・確立することができた。また既に知られた腫瘍型においても、臨床的に意義の大きなグループを新しく認識することができた。さらに、疾患の原因となる遺伝子異常、予後予測に有用なリスク分類、病理診断に有用な診断マーカーも発見することができた。これらの成果の大部分は世界で初めて得られた知見であり学術的意義が大きい。研究の成果により、分類不能・困難な骨軟部腫瘍症例が減少し、より正確な病理診断を行うことができ、医療の質が向上することが期待される。

Research Products

• [Journal Article] ALK-positive Histiocytosis of the Breast (2021)
  • Author(s): Kashima Jumpei、Yoshida Masayuki、Jimbo Kenjiro、Izutsu Koji、Ushiku Tetsuo、Yonemori Kan、Yoshida Akihiko
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 3 Pages: 347-355
  • DOI: 10.1097/pas.0000000000001567
  • Peer Reviewed
• [Journal Article] Recurrent FOS rearrangement in proliferative fasciitis/proliferative myositis (2021)
  • Author(s): Makise Naohiro、Mori Taisuke、Motoi Toru、Shibahara Junji、Ushiku Tetsuo、Yoshida Akihiko
  • Journal Title: Modern Pathology Volume: 34 Issue: 5 Pages: 942-950
  • DOI: 10.1038/s41379-020-00725-2
  • Peer Reviewed
• [Journal Article] Confirmation of NKX3-1 Expression in EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma Using Monoclonal Antibody Immunohistochemistry, RT-PCR, and RNA In Situ Hybridization (2021)
  • Author(s): Yoshida Akihiko、Hashimoto Taiki、Ryo Eijitsu、Yoshida Ken-ichi、Motoi Toru、Yatabe Yasushi、Mori Taisuke
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 4 Pages: 578-582
  • DOI: 10.1097/pas.0000000000001627
  • Peer Reviewed / Open Access
• [Journal Article] Clinicopathologic Characterization of Epithelioid Hemangioendothelioma in a Series of 62 Cases (2021)
  • Author(s): Shibayama Takahiro、Makise Naohiro、Motoi Toru、Mori Taisuke、Hiraoka Nobuyoshi、Yonemori Kan、Watanabe Shun-ichi、Esaki Minoru、Morizane Chigusa、Okuma Tomotake、Kawai Akira、Ushiku Tetsuo、Yatabe Yasushi、Yoshida Akihiko
  • Journal Title: American Journal of Surgical Pathology Volume: 45 Issue: 5 Pages: 616-626
  • DOI: 10.1097/pas.0000000000001660
  • Peer Reviewed / Open Access
• [Journal Article] NKX3-1 Is a Useful Immunohistochemical Marker of EWSR1-NFATC2 Sarcoma and Mesenchymal Chondrosarcoma (2020)
  • Author(s): Yoshida Ken-ichi、Machado Isidro、Motoi Toru、Parafioriti Antonina、Lacambra Maribel、Ichikawa Hitoshi、Kawai Akira、Antonescu Cristina R.、Yoshida Akihiko
  • Journal Title: American Journal of Surgical Pathology Volume: 44 Issue: 6 Pages: 719-728
  • DOI: 10.1097/pas.0000000000001441
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mesenchymal Tumors with RREB1-MRTFB Fusion Involving the Mediastinum: Extra-Glossal Ectomesenchymal Chondromyxoid Tumors? (2020)
  • Author(s): Makise N, Mori T, Kobayashi H, Nakagawa K, Ryo E, Nakajima J, Kohsaka S, Mano H, Aburatani H, Yoshida A and Ushiku T
  • Journal Title: Histopathology Volume: － Issue: 7 Pages: 1023-1031
  • DOI: 10.1111/his.14080
  • Peer Reviewed
• [Journal Article] BRAF V600E mutation is a potential therapeutic target for a small subset of synovial sarcoma. (2020)
  • Author(s): Watanabe S, Shimomura A, Kubo T, Sekimizu M, Seo T, Watanabe SI, Kawai A, Yamamoto N, Tamura K, Kohno T, Ichikawa H, Yoshida A.
  • Journal Title: Mod. Pathol. Volume: - Issue: 9 Pages: 1660-1668
  • DOI: 10.1038/s41379-020-0530-3
  • Peer Reviewed
• [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] Expanding the Phenotypic Spectrum of Mesenchymal Tumors Harboring the EWSR1-CREM Fusion (2019)
  • Author(s): Yoshida Akihiko、Wakai Susumu、Ryo Eijitsu、Miyata Kazuyuki、Miyazawa Masahisa、Yoshida Ken-ichi、Motoi Toru、Ogawa Chitose、Iwata Shintaro、Kobayashi Eisuke、Watanabe Shun-ichi、Kawai Akira、Mori Taisuke
  • Journal Title: The American Journal of Surgical Pathology Volume: 43 Issue: 12 Pages: 1622-1630
  • DOI: 10.1097/pas.0000000000001331
  • Peer Reviewed / Open Access
• [Journal Article] Absence of H3F3A mutation in a subset of malignant giant cell tumor of bone (2019)
  • Author(s): Yoshida Ken-ichi、Nakano Yoshiko、Honda-Kitahara Mai、Wakai Susumu、Motoi Toru、Ogura Koichi、Sano Naoki、Shibata Tatsuhiro、Okuma Tomotake、Iwata Shintaro、Kawai Akira、Ichimura Koichi、Yoshida Akihiko
  • Journal Title: Modern Pathology Volume: 32 Issue: 12 Pages: 1751-1761
  • DOI: 10.1038/s41379-019-0318-5
  • Peer Reviewed / Open Access
• [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] Low-grade endometrial stromal sarcoma with a novel MEAF6-SUZ12 fusion. (2019)
  • Author(s): Makise N, Sekimizu M, Kobayashi E, Yoshida H, Fukayama M, Kato T, Kawai A, Ichikawa H, Yoshida A.
  • Journal Title: Virchows Arch. Volume: 475 Issue: 4 Pages: 527-531
  • DOI: 10.1007/s00428-019-02588-8
  • Peer Reviewed
• [Journal Article] Novel NTRK3 Fusions in Fibrosarcomas of Adults. (2019)
  • Author(s): Yamazaki F, Nakatani F, Asano N, Wakai S, Sekimizu M, Mitani S, Kubo T, Kawai A, Ichikawa H, Yoshida A.
  • Journal Title: American Journal of Surgical Pathology Volume: 43 Issue: 4 Pages: 523-530
  • DOI: 10.1097/pas.0000000000001194
  • Peer Reviewed
• [Journal Article] H3K27me3 deficiency defines a subset of dedifferentiated chondrosarcomas with characteristic clinicopathological features. (2019)
  • Author(s): Makise N, Sekimizu M, Konishi E, Motoi T, Kubo T, Ikoma H, Watanabe SI, Okuma T, Hiraoka N, Fukayama M, Kawai A, Ichikawa H, Yoshida A.
  • Journal Title: Modern Pathology Volume: 32 Issue: 3 Pages: 435-445
  • DOI: 10.1038/s41379-018-0140-5
  • Peer Reviewed / Open Access
• [Presentation] 増殖性筋膜炎/筋炎はFOS遺伝子再構成を有する (2021)
  • Author(s): 牧瀬尚大、森泰昌、元井亨、柴原純二、牛久哲男、吉田朗彦
  • Organizer: 第110回 日本病理学会総会