Identification of biomaker for predicting liver metastasis of colorectal cancer with CAGE analysis

• Project/Area Number: 17K10652
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Juntendo University
• Principal Investigator: Hiromitsu Komiayama 順天堂大学, 医学部, 非常勤講師 (30348982)
• Co-Investigator(Kenkyū-buntansha): 加藤 俊介 順天堂大学, 大学院医学研究科, 教授 (40312657) ; 茂櫛 薫 順天堂大学, 大学院医学研究科, 非常勤講師 (60569292)
• Project Period (FY): 2017-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 腫瘍マーカー / 大腸がん / 肝転移 / 転移予測マーカー / 癌遺伝子 / 採血診断 / 大腸癌 / バイオマーカー / CAGE法 / マイクロダイセクション / 転移メカニズム

Outline of Final Research Achievements

This study aims to develop a predictive marker for liver metastasis in colorectal cancer through blood sample diagnosis. With comprehensive gene expression analysis of the primary cancer sites, we have identified genes that show cancer-specific, metastatic case-specific, and liver metastasis-specific up- or down-regulation. These genes have been thoroughly examined and narrowed down to potential marker candidates. Based on expression analysis with blood samples drawn from patients before and repeatedly after the operation,a few genes whose levels were associated with liver metastasis were selected. These genes belong to the group of genes exhibiting cancer-specific sequence mutations. The relationship between these candidate genes and local recurrence or metastasis to other organs has been confirmed, and the selection of genes as predictive markers for liver metastasis is currently in progress.

Academic Significance and Societal Importance of the Research Achievements

本研究は, 大腸癌の肝転移特異的なゲノム変異に着目, 肝転移特異的変異配列をctDNAから検出・定量する. 一般的マーカー量増大からの悪性化予測ではなく「早期検出が治療選択のために特に重要」な「肝転移」をターゲットとする鋭敏なマーカー開発に目標をおくことは本研究の独自性であると考える.本研究では同時に,患者による多様性がみられる変異配列を個別診断マーカーとして作出・利用する方法の確立を目指す. 現在普及・拡大しつつある遺伝診断の結果から, 個別診断マーカーを取得, 個々の患者に利用するシステムの開発を目指す本研究は、時流に即しつつ独自性が高いものといえる。

Research Products

• [Journal Article] Usefulness of an IL-6 Semi-Quantification Kit in Patients with Perforative Peritonitis (2021)
  • Author(s): Ichikawa R, Sugimoto K, Kure K, Honjo K, Takahashi R, Okazawa Y, Kawai M, Munakata S,Komiyama H, Sakamoto K et al..
  • Journal Title: Juntendo Medical Journal Volume: 67 Issue: 2 Pages: 158-164
  • DOI: 10.14789/jmj.2021.67.JMJ20-OA09
  • NAID: 130008032136
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] Identification of MicroRNA 15b-3p as a Diagnostic Marker for Early Stage of Colorectal Cancer Through Comprehensive RNA Analysis (2021)
  • Author(s): Tsukamoto R, Hosoya M, Fukaya M, Yokoyama N, Kawano S, Sugimoto K, Takahashi M, Sakamoto K, Komiyama H,
  • Journal Title: Juntendo Medical Journal Volume: 67 Issue: 3 Pages: 272-281
  • DOI: 10.14789/jmj.JMJ20-OA12
  • NAID: 130008059636
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] Antitumor effects of novel mAbs against cationic amino acid transporter 1 (CAT1) on human CRC with amplified CAT1 gene (2021)
  • Author(s): Okita K, Hara Y, Okura H, Hayashi H, Sasaki Y, Masuko S, Kitadai E, Masuko K, Yoshimoto S, Komiyama H, Sakamoto K, Masuko T.et al
  • Journal Title: Cancer Sci Volume: 112 Pages: 563-574
  • Peer Reviewed / Open Access
• [Journal Article] Using the polymeric circulating tumor cell chip to capture circulating tumor cells in blood samples of patients with colorectal cancer (2020)
  • Author(s): Kure K, Hosoya M, Ueyama T, Fukaya M, Sugimoto K, Tomiki Y,Ohnaga T, Sakamoto K, Komiyama H.
  • Journal Title: Oncl Lett Volume: 19 Pages: 2286-2294
  • DOI: 10.3892/ol.2020.11335
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-2 as a prognostic factor in patients with incurable stage IV colorectal cancer. (2020)
  • Author(s): Munakata S, Ueyama T, Ishihara H, Komiyama H, Tsukamoto R, Kawai M, Takahashi M, Kojima Y, Tomiki Y,
  • Journal Title: J Gastrointest Cancer. Volume: 2020 Online ahead of print Issue: 1 Pages: 000-000
  • DOI: 10.1007/s12029-020-00392-1
  • Peer Reviewed / Open Access
• [Journal Article] 大腸癌術後肝門部リンパ節転移による閉塞性黄疸に対して胆管ステント留置後に分子標的薬併用全身化学療法を施行した1例. (2020)
  • Author(s): 雨宮 浩太, 百瀬 裕隆, 青木 順, 岡澤 裕, 水越 幸輔, 河野 眞吾, 宗像 慎也, 石山 隼, 杉本 起一, 神山 博彦, 小見山 博光, 高橋 玄, 小島 豊, 奥澤 淳司, 坂本 一博:
  • Journal Title: 癌と化学療法 Volume: 46(4) Pages: 733-735
• [Journal Article] Japan society of clinical oncology/Japanese society of medical oncology-led clinical recommendations on the diagnosis and use of tropomyosin receptor kinase inhibitors in adult and pediatric patients with neurotrophic receptor tyrosine kinase fusion-positive advanced solid tumors, cooperated by the Japanese society of pediatric hematology/oncology. (2020)
  • Author(s): Naito Y, Mishima S, Akagi K, Igarashi A, Ikeda M, Okano, S, Kato S, Takano T, Tsuchihara K, Terashima K, et al.
  • Journal Title: Int J Clin Oncol Volume: 25 Pages: 403-417
  • Peer Reviewed / Open Access
• [Journal Article] Metastatic seeding of human colon cancer cell clusters expressing the hybrid epithelial/mesenchymal state. (2019)
  • Author(s): Mizukoshi K, Okazawa Y, Haeno H, Koyama Y, Sulidan K, Komiyama H, Saeki H, Ohtsuji N, Ito Y, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: Int J Cancer Volume: 146 Issue: 9 Pages: 2547-2562
  • DOI: 10.1002/ijc.32672
  • Peer Reviewed / Open Access
• [Journal Article] Stromal fibroblasts induce metastatic tumor cell clusters via epithelial-mesenchymal plasticity. (2019)
  • Author(s): Matsumura Y, Ito Y, Mezawa Y, Sulidan K, Daigo Y, Hiraga T, Mogushi K, Wali N, Suzuki H, Itoh T, Miyagi Y, Yokose T, Shimizu S, Takano A, Terao Y, Saeki H, Ozawa M, Abe M, Takeda S, Okumura K, Habu S, Hino O, Takeda K, Hamada M, Orimo A.
  • Journal Title: Life Sci Alliance Volume: 2(4):e201900425. Issue: 4 Pages: 1-24
  • DOI: 10.26508/lsa.201900425
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Estrogen receptor-positive ductal carcinoma in situ frequently overexpresses HER2 protein without gene amplification. (2019)
  • Author(s): Horimoto Y, Terao T, Tsutsumi Y, Tanabe M, Mogushi K, Hlaing MT, Sasaki R, Saeki H, Okazaki M, Sonoue H, Arakawa A, Saito M.
  • Journal Title: Am J Surg Pathol Volume: 43(9) Issue: 9 Pages: 1221-1228
  • DOI: 10.1097/pas.0000000000001300
  • Peer Reviewed / Open Access
• [Journal Article] Pharmacological targeting of neutrophil serine proteases prevents lethality in dextran sulfate sodium (DSS)-induced colitis in mice (2018)
  • Author(s): Ro H, Munakata S, Ueyama T, Komiyama H, Takahashi M, Kojima Y, Tomiki Y, Sakamoto K
  • Journal Title: Journal of Gastrointestinal & Digestive System Volume: 8 Issue: 01 Pages: 551-551
  • DOI: 10.4172/2161-069x.1000551
  • Peer Reviewed / Open Access
• [Journal Article] High-sensitivity detection of micrometastases generated by GFP lentivirus-transduced organoids cultured from a patient-derived colon tumor. (2018)
  • Author(s): OkazawaY, Mizukoshi K, KoyamaY, Okubo S, Komiyama H, Kojima Y, Goto M, Habu S, Hino O, Sakamoto K, Orimo A.
  • Journal Title: J Vis Exp Volume: 136(e57374) Issue: 136 Pages: 463-473
  • DOI: 10.3791/57374
  • Peer Reviewed / Open Access
• [Journal Article] COQ2 variants in Parkinson's disease and multiple system atrophy. (2018)
  • Author(s): Mikasa M, Kanai K, Li Y, Yoshino H, Mogushi K, Hayashida A, Ikeda A, Kawajiri S, Okuma Y, Kashihara K, Sato T, Kondo H, Funayama M, Nishioka K, Hattori N.
  • Journal Title: J Neural Transm (Vienna) Volume: - Issue: 6 Pages: 938-944
  • DOI: 10.1007/s00702-018-1885-1
  • Peer Reviewed / Open Access
• [Journal Article] Elucidation of inhibitory effects on metastatic sentinel lymph nodes of breast cancer during One-Step Nucleic Acid Amplification. (2018)
  • Author(s): Horimoto Y, Tanabe M, Kazuno S, Miura Y, Mogushi K, Sonoue H, Arakawa A, Kajino K, Kobayashi T, Saito M.
  • Journal Title: Sci Rep Volume: 8(1):7563 Issue: 1 Pages: 1-7
  • DOI: 10.1038/s41598-018-25911-w
  • Peer Reviewed / Open Access
• [Journal Article] Fatty Acid Binding Protein 4 (FABP4) Overexpression in Intratumoral Hepatic Stellate Cells within Hepatocellular Carcinoma with Metabolic Risk Factors (2018)
  • Author(s): Chiyonobu Norimichi、Shimada Shu、Akiyama Yoshimitsu、Mogushi Kaoru、Itoh Michiko、Akahoshi Keiichi、Matsumura Satoshi、Ogawa Kosuke、Ono Hiroaki、Mitsunori Yusuke、Ban Daisuke、Kudo Atsushi、Arii Shigeki、Suganami Takayoshi、Yamaoka Shoji、Ogawa Yoshihiro、Tanabe Minoru、Tanaka Shinji
  • Journal Title: Am. J. Pathol. Volume: 188 Issue: 5 Pages: 1213-1224
  • DOI: 10.1016/j.ajpath.2018.01.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification and characterization of a novel <i>adenomatous polyposis coli</i> mutation in adult pancreatoblastoma (2018)
  • Author(s): Yamaguchi S, Fujii T, Izumi Y, Fukumura Y, Han M, Yamaguchi H, Akita T, Yamashita C, Kato S, Sekiya T.
  • Journal Title: Oncotarget Volume: 9(12) Issue: 12 Pages: 10818-10827
  • DOI: 10.18632/oncotarget.24017
  • Peer Reviewed / Open Access
• [Journal Article] Survival benefit of lymph node dissection in surgery for colon cancer in elderly patients:multicenter propensity score-matched study in Japan. (2018)
  • Author(s): Takahashi M, Niitsu H, Sakamoto K, Hinoi T, Hattori M, Goto M, Bando H, Hazama S, Maeda K, Okita K, Horie H, Watanabe M; Japan Society of Laparoscopic Colorectal Surgery.
  • Journal Title: Asian J Endosc Surg Volume: 2018 Mar 30 Issue: 4 Pages: 1-9
  • DOI: 10.1111/ases.12474
  • Peer Reviewed
• [Journal Article] High-sensitivity detection of micrometastases generated by GFP lentivirus-transduced organoidscultured from a patient-derived colon tumor (2018)
  • Author(s): Okazawa Y, Mizukoshi K, Koyama Y, Okubo S, Komiyama H, Kojima Y, Goto M, Habu S, Hino O,Sakamoto K, Orimo A.
  • Journal Title: Journal of Visualized Experiments（JoVE） in press Volume: --
  • Peer Reviewed
• [Journal Article] Molecular and clinical features of the TP53 signature gene expression profile in early-stage breast cancer. (2018)
  • Author(s): Yamaguchi S, Takahashi S, Mogushi K, Izumi Y, Nozaki Y, Nomizu T, Kakugawa Y, Ishida T, Ohuchi N, Ishioka C, Kato S.
  • Journal Title: Oncotarget Volume: 9(18) Issue: 18 Pages: 14193-14206
  • DOI: 10.18632/oncotarget.24447
  • Peer Reviewed / Open Access
• [Journal Article] Minimally Invasive Surgery for Colorectal Cancer (2017)
  • Author(s): Sakamoto K, Tsukamoto R, Kawano S, Kawai M, Niwa K, Ishiyama S, Sugimoto K, Kamiyama H, Komiyama H, Takahashi M, Kojima Y, Goto M, Okuzawa A, Tomiki Y:
  • Journal Title: Juntendo Medical Journal Volume: 63 Issue: 5 Pages: 384-392
  • DOI: 10.14789/jmj.63.384
  • NAID: 130006219695
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access
• [Journal Article] Propensity Score Analysis in the Comparison of Long-Term Outcomes for Locally Advanced Colon Cancer Between Laparoscopic Colectomy and Open Colectomy (2017)
  • Author(s): Sugimoto K, Sakamoto K, Ichikawa R, Kure K, Honjo K, Ro H, Takahashi R, Kawano, Niwa K, Ishiyama S, Kamiyama H, Komiyama H, Takahashi M, Kojima Y, Goto M, Okuzawa A, Ishibiki Y, Tomiki Y
  • Journal Title: Juntendo Medical Journal Volume: 63 Issue: 4 Pages: 264-272
  • DOI: 10.14789/jmj.63.264
  • NAID: 130006106309
  • ISSN: 2187-9737, 2188-2126
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Immune-complex level of cofilin-1 in sera is associated with cancer progression and poor prognosis in pancreatic cancer. (2017)
  • Author(s): Satoh M, Takano S, Sogawa K, Noda K, Yoshitomi H, Ishibashi M, Mogushi K, Takizawa H, Otsuka M, Shimizu H, Miyazaki M, Nomura F.
  • Journal Title: Cancer Sci. Volume: 印刷中 Issue: 4 Pages: 795-803
  • DOI: 10.1111/cas.13181
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 直腸癌手術におけるdiverting stomaの有用性の検討 (2022)
  • Author(s): 百瀨裕隆、髙橋玄、井祐樹、河口恵、小針文、塚本亮一、本庄薫平、岡澤裕、髙橋里奈、河合雅也、河野眞吾、宗像慎也、杉本起一、小島豊、小見山博光、冨木裕一、坂本一博
  • Organizer: 第122回日本外科学会定期学術集会
• [Presentation] Detection of circulating tumor cellsin blood samples of colorectal cancer patients using the polymeric CTC chip (2020)
  • Author(s): 深谷 緑・呉 一眞・大永 崇・細谷 理樹・杉本 起一・坂本 一博・小見山 博光
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 網羅的解析を用いた新規結腸癌診断マーカーの探索. (2019)
  • Author(s): 塚本亮一, 小見山博光, 河野眞吾, 河合雅也, 高橋玄, 小島豊, 冨木裕一, 坂本一博:
  • Organizer: 第57回日本癌治療学会学術集会, 福岡.
• [Presentation] 大腸癌における原発巣および血漿中遊離DNAのCHFR遺伝子メチル化測定の意義. (2019)
  • Author(s): 杉本起一, 百瀬裕隆, 岡澤 裕, 高橋里奈, 水越幸輔, 盧 尚志, 河合雅也, 宗像慎也, 神山博彦, 高橋 玄, 小島 豊, 冨木裕一, 福永 哲, 梶山美明, 坂本一博:
  • Organizer: 第57回日本癌治療学会学術集会, 福岡.
• [Presentation] 患者大腸癌細胞集団の中間型上皮間葉移行を介した浸潤・転移機構. (2019)
  • Author(s): 水越幸輔，岡澤 裕，波江野 洋，小山 侑，大久保捷奇，Kaidiliavi Sulidan，伊藤恭彦，小見山博光，杉本起一，小島 豊，五藤倫敏，垣生園子，樋野興夫，折茂 彰，坂本一博:
  • Organizer: 第30回日本消化器癌発生学会総会，横浜.
• [Presentation] 網羅的解析を用いた新規結腸癌診断マーカーの探索 (2018)
  • Author(s): 塚本 亮一, 小見山 博光, 細谷 理樹, 河野 眞吾, 河合 雅也, 高橋 玄, 小島 豊, 冨木 裕一, 坂本 一博
  • Organizer: 日本外科学会定期学術集会
• [Presentation] SLC7A1に対するモノクローナル抗体 大腸癌組織における遺伝子発現評価と,抗体の癌細胞株に対する傷害活性(Monoclonal antibodies against SLC7A1: assessment of gene expression and cytotoxicity in colorectal cancer) (2018)
  • Author(s): 深谷 緑, 小見山 博光, 杉本 起一, 神山 博彦, 益子 高, 坂本 一博
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 大腸癌における循環血液中p14遺伝子DNAメチル化測定の意義 (2018)
  • Author(s): 杉本 起一, 萩原 俊昭, 神山 博彦, 高橋 玄, 小島 豊, 冨木 裕一, 福永 哲, 梶山 美明, 川崎 誠治, 坂本 一博
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] Semaphorin 3C has a possibility of a new prognostic marker in colorectal cancer. (2017)
  • Author(s): Kawano S, Amemiya K, Komiyama H, Sakamoto K et al.
  • Organizer: 110th AACR, Washington DC
  • Int'l Joint Research
• [Presentation] Production of monoclonal antibodies against amino acid transporter SLC7A1 to develop novel therapy for colorectal cancer. (2017)
  • Author(s): Fukaya M, Komiyama H, Sugimoto K, Kamiyama H, Sakamoto K:
  • Organizer: 第76回日本癌学会学術総会, 横浜
• [Presentation] Identification of a novel diagnostic marker for colon cancer through comprehensive microRNA analysis. (2017)
  • Author(s): Tsukamoto R, Komiyama H, Hosoya M, Kure K, Okazawa Y, Mizukoshi K, Fukaya M, Sugimoto K, Kamiyama H, Tomiki Y, Sakamoto K:
  • Organizer: 第76回日本癌学会学術総会, 横浜
• [Presentation] StageII大腸癌のhigh risk 因子の再検討. (2017)
  • Author(s): 河野眞吾 雨宮浩太 茂木俊介 塚本亮一 河合雅也 杉本起一 神山博彦 小見山博光 高橋 玄 小島 豊 冨木裕一 福永 哲 梶山美明 川崎誠治 坂本一博
  • Organizer: 第79回日本臨床外科学会総会, 東京
• [Presentation] StageII結腸癌における術後補助化学療法の有効性に関する検討-Propensity score matching analysis. (2017)
  • Author(s): 杉本 起一，塚本 亮一，丹羽 浩一郎，石山 隼，神山 博彦，小見山 博光，福永 哲，梶山 美明，川崎 誠治，坂本 一博
  • Organizer: 日本消化器外科学会総会, 金沢
• [Presentation] 大腸癌同時性肝転移症例におけるGlasgow Prognostic Score (GPS) を用いた予後評価 (2017)
  • Author(s): 杉本起一，市川亮介，高橋里奈，盧尚志,河野眞吾，丹羽浩一郎，石山 隼，神山博彦，小見山博光,高橋玄,小島豊,五藤倫敏,奥澤淳司,冨木裕一,吉本次郎,今村宏,石崎陽一,川崎誠治,福永哲,梶山美明,坂本一博.
  • Organizer: 第117回日本外科学会定期学術集会, 横浜
• [Remarks] 順天堂大学下部消化管外科学(消化器外科学講座)
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学下部消化管外科学（消化器外科学講座）
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学大学院 下部消化管外科学
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学大学院 下部消化管外科学
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/
• [Remarks] 順天堂大学大学院 下部消化管外科学（消化器外科学講座）
  • URL: https://www.juntendo.ac.jp/graduate/laboratory/labo/kabusyoukakan/