Clinicopathological and molecular characterization of tumors with various directions of differentiation

• Project/Area Number: 20K16167
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Chiba Cancer Center (Research Institute) (2021-2022); The University of Tokyo (2020)
• Principal Investigator: MAKISE Naohiro 千葉県がんセンター(研究所), 臨床病理部, 医長 (70815373)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肉腫 / 病理 / 融合遺伝子 / 免疫染色 / FISH / 次世代シーケンサー

Outline of Research at the Start

本研究の目的は、様々な分化方向を示すような腫瘍の遺伝子変異、病理像、臨床像を明らかにすることである。
これまで分類が困難であった腫瘍に対して既知の遺伝子変異、あるいは新規の遺伝子変異/融合遺伝子を発見することを試みる。
これにより、より適切に腫瘍を分類すること、診断に有用なマーカーを発見すること、治療標的候補を提案すること、を目指す。

Outline of Final Research Achievements

I found FOS gene rearrangement in proliferative fasciitis/myositis. I found a homozygous deletion of the EED gene and loss of H3K27me3 in dedifferentiated chordomas with heterologous rhabdomyoblastic differentiation. I found the EWSR1::NFATC2 fusion gene and characteristic radiological features in a sarcoma previously diagnosed as Ewing-like adamantinoma. I reported a DICER1 mutant sarcoma showing differentiation into rhabdomyosarcoma.
I have also been involved in other reports of RREB1::MRTFB tumors, NTRK-rearranged mesenchymal neoplasms, phosphaturic mesenchymal tumors, and epithelioid hemangioendotheliomas with neuroendocrine differentiation.

Academic Significance and Societal Importance of the Research Achievements

本研究により様々な分化方向を示すような腫瘍の臨床病理像、分子異常を明らかにした。EWSR1::NFATC2肉腫に特徴的な放射線像を報告した。DICER1変異肉腫に特徴的な臨床像、組織像を報告した。増殖性筋膜炎/筋炎におけるc-FOS免疫染色、脱分化型脊索腫におけるH3K27me3免疫染色などの診断的有用性を報告した。また、リン酸塩尿性間葉系腫瘍やNTRK融合腫瘍の臨床病理放射線像の報告にも携わった。これらは正確な病理診断に寄与することが期待できる。
NTRK融合腫瘍には標的治療が期待できる。DICER1変異肉腫やH3K27me3消失脱分化型脊索腫に対する標的治療の可能性についても論じた。

Research Products

• [Journal Article] Dramatic response to entrectinib in a patient with malignant peripheral nerve sheath tumor harboring novel SNRNP70-NTRK3 fusion gene (2023)
  • Author(s): Kobayashi H, Makise N, Shinozaki-Ushiku A, Zhang L, Ishibashi Y, Ikegami M, Tsuda Y, Kohsaka S, Ushiku T, Oda K, Miyagawa K, Aburatani H, Mano H, Tanaka S.
  • Journal Title: Genes Chromosomes Cancer. Volume: 62 Issue: 1 Pages: 47-51
  • DOI: 10.1002/gcc.23089
  • Peer Reviewed
• [Journal Article] Imaging findings of NTRK?rearranged spindle cell neoplasms: A case series (2023)
  • Author(s): Kobayashi Hiroshi、Teramura Yasuyo、Yamashita Kyoko、Makise Naohiro、Ae Keisuke、Tanaka Sakae
  • Journal Title: Molecular and Clinical Oncology Volume: 18 Issue: 3
  • DOI: 10.3892/mco.2023.2610
  • Peer Reviewed
• [Journal Article] Subcutaneous axillary primary epithelioid hemangioendothelioma: report of a rare case (2022)
  • Author(s): Niwa Takayoshi、Konishi Takaaki、Sasahara Asako、Sato Ayaka、Morizono Arisa、Harada Mayumi、Nishioka Kotoe、Fukuoka Osamu、Makise Naohiro、Saito Yuki、Ando Mizuo、Yoshimoto Takako、Shikama Takeshi、Yamashita Satoshi、Tanabe Masahiko、Seto Yasuyuki
  • Journal Title: Surgical Case Reports Volume: 8 Issue: 1 Pages: 1-1
  • DOI: 10.1186/s40792-022-01521-7
  • Peer Reviewed
• [Journal Article] Giant filiform polyposis with high-grade dysplasia: A case report and review of the literature (2022)
  • Author(s): Kasuga So、Anzai Hiroyuki、Makise Naohiro、Sonoda Hirofumi、Nagai Yuzo、Abe Shinya、Yokoyama Yuichiro、Ozawa Tsuyoshi、Emoto Shigenobu、Murono Koji、Sasaki Kazuhito、Kawai Kazushige、Nozawa Hiroaki、Ushiku Tetsuo、Ishihara Soichiro
  • Journal Title: Annals of Medicine & Surgery Volume: 82
  • DOI: 10.1016/j.amsu.2022.104433
  • Peer Reviewed
• [Journal Article] Loss of H3K27 trimethylation in a distinct group of de‐differentiated chordoma of the skull base (2022)
  • Author(s): Makise Naohiro、Shimoi Tatsunori、Sunami Kuniko、Aoyagi Yasuko、Kobayashi Hiroshi、Tanaka Shota、Kawai Akira、Yonemori Kan、Ushiku Tetsuo、Yoshida Akihiko
  • Journal Title: Histopathology Volume: 82 Issue: 3 Pages: 420-430
  • DOI: 10.1111/his.14823
  • Peer Reviewed
• [Journal Article] Atypical Neurofibromatous Neoplasm with Uncertain Biologic Potential in the Posterior Mediastinum of a Young Patient with Neurofibromatosis Type 1: A Case Report (2022)
  • Author(s): Miyamoto K, Kobayashi H, Zhang L, Tsuda Y, Makise N, Yasunaga Y, Ikemura M, Nakai Y, Shibata E, Ushiku T, Tanaka S.
  • Journal Title: Case Rep Oncol . Volume: 15 Issue: 3 Pages: 988-994
  • DOI: 10.1159/000526844
  • Peer Reviewed / Open Access
• [Journal Article] Utility of Multimodality Approach Including Systemic FGF23 Venous Sampling in Localizing Phosphaturic Mesenchymal Tumors. (2022)
  • Author(s): Kato H, Koga M, Kinoshita Y, Hidaka N, Hoshino Y, Takashi Y, Arai M, Kobayashi H, Katsura M, Nakamoto Y, Makise N, Ushiku T, Hoshi K, Nangaku M, Makita N, Fukumoto S, Ito N.
  • Journal Title: J Endocr Soc Volume: 24 Issue: 2
  • DOI: 10.1210/jendso/bvac181
  • Peer Reviewed / Open Access
• [Journal Article] Imaging characteristics of NTRK-rearranged spindle cell neoplasm of the soft tissue: A case report. (2022)
  • Author(s): Takamiya Akihiro、Ishibashi Yuki、Makise Naohiro、Hirata Makoto、Ushiku Tetsuo、Tanaka Sakae、Kobayashi Hiroshi.
  • Journal Title: Journal of Orthopaedic Science Volume: S0949-2658(21) Issue: 6 Pages: 00367-5
  • DOI: 10.1016/j.jos.2021.11.002
  • Peer Reviewed / Open Access
• [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] 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] Fat-forming solitary fibrous tumor of the sacrum: A case report and literature review (2021)
  • Author(s): Furuta Toshihiro、Nakai Yudai、Gonoi Wataru、Kurokawa Ryo、Okimoto Naomasa、Sakamoto Naoya、Fukuchi Haruyuki、Kobayashi Hiroshi、Makise Naohiro、Abe Osamu
  • Journal Title: Radiology Case Reports Volume: 16 Issue: 7 Pages: 1874-1877
  • DOI: 10.1016/j.radcr.2021.04.052
  • Peer Reviewed
• [Journal Article] Skeletal <i>EWSR1‐NFATC2</i> sarcoma previously diagnosed as Ewing‐like adamantinoma: A case report and literature review emphasizing its unique radiological features (2021)
  • Author(s): Makise Naohiro、Yoshida Ken‐Ichi、Iijima Takuo、Yoshida Akihiko、Ushiku Tetsuo、Ishida Tsuyoshi
  • Journal Title: Pathology International Volume: 71 Issue: 9 Pages: 614-620
  • DOI: 10.1111/pin.13135
  • Peer Reviewed
• [Journal Article] Hemangioma of the Rib Mimicking Chondrosarcoma: A Report of Two Cases and Literature Review. (2021)
  • Author(s): Tsuda Y, Kobayashi H, Makise N, Zhang L, Shinoda Y, Ushiku T, Tanaka S.
  • Journal Title: Case Rep Orthop. Volume: - Pages: 1-5
  • DOI: 10.1155/2021/9996380
  • Peer Reviewed
• [Journal Article] Scapular Angiomatoid Fibrous Histiocytoma with EWSR1-CREB1 Fusion in an Adult Patient (2021)
  • Author(s): Kobayashi H, Makise N, Shinozaki-Ushiku A, Ishibashi Y, Ikegami M, Kohsaka S, Ushiku T, Oda K, Miyagawa K, Aburatani H, Mano H, Tanaka S.
  • Journal Title: Case Rep Orthop Volume: 2021 Pages: 9434222-9434222
  • DOI: 10.1155/2021/9434222
  • Peer Reviewed / Open Access
• [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] Surgical margin for phosphaturic mesenchymal tumors in soft tissues: An analysis of the radiological histopathological correlation (2020)
  • Author(s): Kobayashi Hiroshi、Makise Naohiro、Ito Nobuaki、Koga Minae、Zhang Liuzhe、Ishibashi Yuki、Ikegami Masachika、Shinoda Yusuke、Akiyama Toru、Ushiku Tetsuo、Tanaka Sakae
  • Journal Title: Journal of Orthopaedic Science Volume: - Issue: 5 Pages: 870-877
  • DOI: 10.1016/j.jos.2020.07.006
  • Peer Reviewed
• [Journal Article] An autopsy case of prostatic rhabdomyosarcoma with DICER1 hotspot mutation (2020)
  • Author(s): Miyama Yu、Makise Naohiro、Miyakawa Jimpei、Kume Haruki、Fukayama Masashi、Ushiku Tetsuo
  • Journal Title: Pathology International Volume: 71 Issue: 1 Pages: 102-108
  • DOI: 10.1111/pin.13042
  • Peer Reviewed
• [Journal Article] Genetic Testing Distinguishes Multiple Chondroid Chordomas with Neuraxial Bone Metastases from Multicentric Tumors (2020)
  • Author(s): Kobayashi Hiroshi、Shin Masahiro、Makise Naohiro、Shinozaki-Ushiku Aya、Ikegami Masachika、Taniguchi Yuki、Shinoda Yusuke、Kohsaka Shinji、Ushiku Tetsuo、Oda Katsutoshi、Miyagawa Kiyoshi、Aburatani Hiroyuki、Mano Hiroyuki、Tanaka Sakae
  • Journal Title: Case Reports in Genetics Volume: 2020 Pages: 1-6
  • DOI: 10.1155/2020/8877722
  • Peer Reviewed / Open Access
• [Presentation] 頭蓋底発生の脱分化型脊索腫にはH3K27トリメチル化消失を伴う特異な一群がある (2023)
  • Author(s): 牧瀬尚大、下井辰徳、角南久仁子、青柳康子、小林寛、田中將太、川井章、米盛勧、牛久哲男、吉田朗彦
  • Organizer: 第112回病理学会総会
• [Presentation] ユーイング様アダマンチノーマはEWSR1-NFATC2肉腫か ：1例報告とその文献的解析 (2022)
  • Author(s): 牧瀬尚大 , 吉田研一 , 吉田朗彦 , 牛久哲男 , 石田剛
  • Organizer: 第111回病理学会総会
• [Presentation] EWSR1::NFATC2 肉腫の 1 例 (2022)
  • Author(s): 竹田直生,牧瀬尚大,高橋 司,小高亜紀子,加藤弘志,及川麻理子,杉山孝弘,川名秀忠,荒木章伸,伊丹真紀子
  • Organizer: 第 61 回日本臨床細胞学会秋期大会
• [Presentation] ユーイング様アダマンチノーマはEWSR1-NFATC2肉腫か ：1例報告とその文献的解析 (2022)
  • Author(s): 牧瀬尚大, 吉田研一, 吉田朗彦, 牛久哲男, 石田剛
  • Organizer: 第111回病理学会総会
• [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回病理学会総会
• [Presentation] 新たな未分化円形細胞肉腫（CIC、BCOR、EWSR1-NFATC2 肉腫） (2021)
  • Author(s): 牧瀬尚大, 牛久哲男
  • Organizer: 第110回病理学会総会
  • Invited
• [Presentation] 脊索腫とその亜型 (2021)
  • Author(s): 牧瀬尚大, 牛久哲男
  • Organizer: 第62回日本臨床細胞学会総会
  • Invited
• [Presentation] RREB1-MRTFB融合縦隔腫瘍：舌外外胚葉間葉性軟骨粘液様腫瘍か？ (2020)
  • Author(s): 牧瀬尚大,森泰昌,梁英実,高阪真路,間野博行,油谷浩幸,吉田朗彦,牛久哲男
  • Organizer: 第109回日本病理学会総会
• [Book] 病理と臨床 2023年臨時増刊号（41巻）病理診断クイックリファレンス2023（分担執筆, 範囲:脂肪肉腫（高分化型/脱分化型,粘液型)、平滑筋肉腫） (2023)
  • Author(s): 『病理と臨床』編集委員会
  • Total Pages: 364
  • Publisher: 文光堂
• [Book] 骨腫瘍 (2021)
  • Author(s): 小田義直、?田朗彦
  • Total Pages: 272
  • Publisher: 文光堂
  • ISBN: 9784830622557
• [Book] 悪性軟部腫瘍 (2021)
  • Author(s): 長谷川匡、小田義直
  • Total Pages: 336
  • Publisher: 文光堂
  • ISBN: 9784830622564