| Project/Area Number |
18K16321
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 55020:Digestive surgery-related
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| Research Institution | Kumamoto University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥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)
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| Keywords | 胃癌 / 腹膜播種 / ゲノム解析 / 次世代シークエンス / Exsosome / 腫瘍免疫 / 腫瘍微小環境 / 腹膜播種再発 / Exosome / 癌関連繊維芽細胞 / バイオマーカー / リキッドバイオプシー / 悪性腹水 |
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| Outline of Final Research Achievements |
We identified distinct alterations in peritoneal carcinomatosis versus primary lesion in patients with gastric adenocarcinoma (GAC). Alterations associated with aggressive peritoneal carcinomatosis phenotypes emerged with increased mutations in TP53, CDH1, TAF1 and KMT2C, higher level of ’clock-like’ mutational signature, increase in whole-genome doublings, chromosomal instability (particularly, copy number losses), reprogrammed microenvironment, enriched cell cycle pathways, MYC activation and impaired immune response. Integrated analysis identified two main molecular subtypes: ’mesenchymal-like’ and ’epithelial-like’ with discriminating response to chemotherapy (31% vs 71%).
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| Academic Significance and Societal Importance of the Research Achievements |
胃癌の腹膜播種は最も多くみられる転移、再発形式であり、その予後は極めて不良である。腹膜播種の分子生物学的発生メカニズムを解明し、早期診断のバイオマーカーや新規治療戦略を同定することで胃癌の予後を向上させると思われる。我々は胃癌腹膜播種症例の腹水細胞のゲノム解析を行い、腹膜に転移した悪性細胞に特徴的な遺伝子変異を同定した。さらに、免疫抑制に関与するTIM-3の発現が腹水腫瘍細胞の免疫逃避に関与している可能性が明らかにされた、あらたな免疫治療の創薬が期待される
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