Clinicopathological and molecular characterization of bone and soft tissue tumors with aberrant histone modification

• Project/Area Number: 18K15110
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: The University of Tokyo (2019); National Cancer Center Japan (2018)
• Principal Investigator: MAKISE Naohiro 東京大学, 大学院医学系研究科(医学部), 助教 (70815373)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 肉腫 / 病理 / 脱分化 / 異所性分化 / ヒストン / 免疫染色 / FISH / 次世代シーケンサー

Outline of Final Research Achievements

We discovered that SUZ12 or EED mutation and H3K27me3 loss, which were thought to be specific for malignant peripheral nerve sheath tumors, were also seen in subsets of dedifferentiated liposarcomas, extraskeletal osteosarcomas, and dedifferentiated chondrosarcomas. H3K27me3 loss was associated with heterologous differentiation.
We discovered a case of low-grade endometrial stromal sarcoma with a novel fusion of histone modifiers, MEAF6 and SUZ12. We also discovered two cases of mesenchymal tumors with RREB1-MRTFB fusion involving the mediastinum.

Academic Significance and Societal Importance of the Research Achievements

SUZ12,EED遺伝子変異とH3K27me3消失が悪性末梢神経鞘腫瘍以外の骨軟部腫瘍でも見られることを発見した。これにより、H3K27me3消失が色々な腫瘍の脱分化や異所性分化に関わっていること、診断の際に注意が必要なことを明らかにした。SUZ12,EED遺伝子変異は、治療標的の候補となる可能性がある。
新規融合遺伝子MEAF6-SUZ12を有する低悪性度子宮内膜間質肉腫1例と、頭頚部外発生のRREB1-MRTFB融合間葉系腫瘍2例を報告し、骨軟部腫瘍のより適切な分類に寄与した。

Research Products

• [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] 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] 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] 肉腫の脱分化・異所性分化とH3K27me3消失 (2020)
  • Author(s): 牧瀬尚大
  • Organizer: 第39回日本画像医学会
  • Invited
• [Presentation] H3K27me3の消失した脱分化型軟骨肉腫は 特徴的な臨床病理像を示す小群を形成する (2018)
  • Author(s): 牧瀬尚大、関水壮哉、小西英一、元井亨、久保崇、平岡伸介、深山正久、川井章、市川仁、吉田朗彦
  • Organizer: 第107回日本病理学会
• [Presentation] 脱分化ないし異所性分化を示す肉腫 におけるMDM2増幅とH3K27me3消失の 診断的意義に関する研究 (2018)
  • Author(s): 牧瀬尚大
  • Organizer: 第107回日本病理学会