婦人科がん薬物療法後のがんゲノム・RNA解析による薬剤耐性の解明

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19H03795
• Research Institution: Tohoku University
• Principal Investigator: 八重樫 伸生 東北大学, 医学系研究科, 教授 (00241597)
• Co-Investigator(Kenkyū-buntansha): 安田 純 地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), 発がん制御研究部, 部長 (00281684) ; 島田 宗昭 東北大学, 医学系研究科, 准教授 (40362892) ; 徳永 英樹 東北大学, 大学病院, 准教授 (30595559) ; 石橋 ますみ 東北大学, 大学病院, 助教 (20821383)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 婦人科がん / 薬剤耐性 / がんゲノム解析 / メタボローム / 循環腫瘍DNA

Outline of Annual Research Achievements

2021年度は、超高速液体クロマトグラフ質量分析計を活用して、最大628種類の代謝物をBiocrates MxP(R) Quant 500 kitを用い、正規化が安定して可能な条件下で卵巣がん患者80例の血漿内代謝物を絶対定量解析した。同手法で解析した健常人コホート8000人のメタボローム解析データおよび調査票属性データから、年齢・身長・体重をマッチさせた対照を抽出し比較検討した。卵巣がん患者血漿中のメタボローム解析では健常人に比較し77 種類の代謝物が有意に上昇し、114種類で有意に下降していた。主成分分析により、健常人と卵巣がん患者の代謝物の分布に違いがあることが見出された。直交部分最小二乗法による判別分析の結果、特にホスファチジルコリンの減少とトリグリセリドの上昇が卵巣がん患者と健常人の代謝物プロファイル上、明確な差となって現れた。予後情報と各代謝物との相関解析では、トリプトファンと尿毒症毒素であるキヌレニンとの比が予後と相関した。再発卵巣がん患者11名に対して、経過観察時の採血検体より循環腫瘍DNA(ctDNA)を抽出し、測定した。各症例において初回手術時検体から同定した、患者特異的変異を標的としたドロップレット・デジタルPCRを用いて、血清腫瘍マーカー及びCT検査所見に基づく再発診断との整合性を検証した。その結果、血清腫瘍マーカーCA125の上昇タイミングより早くctDNAが計測されることと、腫瘍量との相関関係を見出し、精確かつ鋭敏な再発診断ツールとしての可能性を見出した。卵巣がん細胞株においてクロマチンリモデリング分子の一つであるCHD4の研究をおこなった。CHD4の抑制及び過剰発現実験により、CHD4が白金製剤抵抗性を制御する分子機構を明らかにした。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women. (2022)
  • Author(s): Onuki M, Yamamoto K, Yahata H, Kanao H, Yokota H, Kato H, Shimamoto K, Takehara K, Kamiura S, Tsuda N, Takei Y, Shigeta S, (15名,) Yaegashi N, Matsumoto K; MINT Study Group.
  • Journal Title: Cancer Sci. Volume: 113(4) Pages: 1428-1434
  • DOI: 10.1111/cas.15270.
  • Peer Reviewed / Open Access
• [Journal Article] Rethinking the significance of surgery for uterine cervical cancer. (2022)
  • Author(s): Shimada M, Tsuji K, Shigeta S, Nagai T, Watanabe Z, Tokunaga H, Kigawa J, Yaegashi N.
  • Journal Title: J Obstet Gynaecol Res. Volume: 48(3) Pages: 576-586
  • DOI: 10.1111/jog.15112.
  • Peer Reviewed / Open Access
• [Journal Article] Changes in HPV16/18 Prevalence among Unvaccinated Women with Cervical Intraepithelial Neoplasia in Japan: Assessment of Herd Effects following the HPV Vaccination Program. (2022)
  • Author(s): Onuki M, Yamamoto K,（9名）Shigeta S, Nakai H, Yoshida H, Motohara T, Kato T, Nakamura K, Hamanishi J, Tasaka N, Ishikawa M, Kado N, Taira Y, Mori M, Iwata T, Takahashi F, Kukimoto I, Yoshikawa H, Yaegashi N, Matsumoto K, For The Mint Study Group.
  • Journal Title: Vaccines (Basel) Volume: 10(2) Pages: 188
  • DOI: 10.3390/vaccines10020188.
  • Peer Reviewed / Open Access
• [Journal Article] Co-expression of nuclear heterogeneous nuclear ribonucleic protein K and estrogen receptor alpha in endometrial cancer. (2022)
  • Author(s): Miki Y, Iwabuchi E, Takagi K, Suzuki T, Sasano H, Yaegashi N, Ito K.
  • Journal Title: Pathol Res Pract. Volume: 231 Pages: 153795
  • DOI: 10.1016/j.prp.2022.153795.
  • Peer Reviewed / Open Access
• [Journal Article] Discrepancies in pathological diagnosis of endometrial stromal sarcoma: a multi-institutional retrospective study from the Japanese Clinical Oncology Group. (2022)
  • Author(s): Yoshida H, Kikuchi A, Tsuda H, Sakamoto A, Fukunaga M, Kaku T, Yoshida M, Shikama A, Kogata Y, Terao Y, Tanikawa M, Yasuoka T, Chiyoda T, Miyamoto T, Okadome M, Nakamura T, Enomoto T, Konno Y, Yahata H, Hirata Y, Aoki Y, Tokunaga H, Usui H, Yaegashi N.
  • Journal Title: Hum Pathol. Volume: S0046-8177(22)00073-9 Pages: -
  • DOI: 10.1016/j.humpath.2022.03.007.
• [Journal Article] Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual Patient Report for 2018 and Annual Treatment Report for 2013. (2022)
  • Author(s): Nagase S, Ohta T, Takahashi F, Yamagami W, Yaegashi N; Board Members of the 2020 Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology.
  • Journal Title: J Obstet Gynaecol Res. Volume: 48(3) Pages: 541-552
  • DOI: 10.1111/jog.15134.
  • Peer Reviewed / Open Access
• [Journal Article] Association between hospital treatment volume and survival of women with gynecologic malignancy in Japan: a JSOG tumor registry-based data extraction study. (2022)
  • Author(s): Machida H, Matsuo K, Oba K, Aoki D, Enomoto T, Okamoto A, Katabuchi H, Nagase S, Mandai M, Yaegashi N, Yamagami W, Mikami M.
  • Journal Title: J Gynecol Oncol. Volume: 33(1) Pages: e3
  • DOI: 10.3802/jgo.2022.33.e3.
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of postoperative adjuvant therapy in 102 patients with gastric-type mucinous carcinoma of the uterine cervix: A multi-institutional study. (2022)
  • Author(s): Nishio S, Matsuo K, Nasu H, Murotani K, Mikami Y, Yaegashi N, Satoh T, Okamoto A, Ishikawa M, Miyamoto T, Mandai M, Takehara K, Yahata H, Takekuma M, Ushijima K.
  • Journal Title: Eur J Surg Oncol. Volume: S0748-7983(22)00129-9 Pages: -
  • DOI: 10.1016/j.ejso.2022.03.007.
  • Peer Reviewed / Open Access
• [Journal Article] MicroRNA-152 Regulates Endometrial Serous Carcinoma Cell Motility by Suppressing Matrix Metalloproteinase 10 Expression. (2022)
  • Author(s): Shigeta S, Watanabe Y, Suzuki F, Nagase S, Shibuya Y, Ishibashi M, Nagai T, Shiga N, Toyoshima M, Tokunaga H, Shimada M, Yaegashi N.
  • Journal Title: Tohoku J Exp Med. Volume: 256(3) Pages: 249-258
  • DOI: 10.1620/tjem.256.249.
  • Peer Reviewed / Open Access
• [Journal Article] The efficacy and safety profile of 2-weekly dosing of bevacizumab-containing chemotherapy for platinum-resistant recurrent ovarian cancer. (2021)
  • Author(s): Sekine M, Enomoto T, Watanabe Y, Katabuchi H, Yaegashi N, Aoki D.
  • Journal Title: Int J Clin Oncol. Volume: 26(11) Pages: 2123-2129
  • DOI: 10.1007/s10147-021-01996-8.
  • Peer Reviewed / Open Access
• [Journal Article] Surveillance of radical hysterectomy for early-stage cervical cancer in the early experienced period of minimally invasive surgery in Japan. (2021)
  • Author(s): Ohta T, Nagase S, Okui Y, Enomoto T, Yamagami W, Mikami M, Tokunaga H, Ino K, Ushijima K, Shozu M, Tashiro H, Mandai M, Miyamoto S, Morishige KI, Yoshida Y, Yoshino K, Saito T, Kobayashi E, Kobayashi H, Takekuma M, Terai Y, Fujii T, Kanao H, Aoki D, Katabuchi H, Yaegashi N.
  • Journal Title: Int J Clin Oncol. Volume: 26(12) Pages: 2318-2330
  • DOI: 10.1007/s10147-021-02017-4.
  • Peer Reviewed / Open Access
• [Journal Article] Annual report of the Committee on Gynecologic Oncology, the Japan Society of Obstetrics and Gynecology: Annual patient report for 2017 and annual treatment report for 2012. (2021)
  • Author(s): Nagase S, Ohta T, Takahashi F, Yaegashi N; Board members of the 2020 Committee on Gynecologic Oncology of the Japan Society of Obstetrics and Gynecology.
  • Journal Title: J Obstet Gynaecol Res. Volume: 47(5) Pages: 1631-1642
  • DOI: 10.1111/jog.14724.
  • Peer Reviewed / Open Access
• [Journal Article] Wide-Targeted Metabolome Analysis Identifies Potential Biomarkers for Prognosis Prediction of Epithelial Ovarian Cancer. (2021)
  • Author(s): Hishinuma E, Shimada M, Matsukawa N, Saigusa D, Li B, Kudo K, Tsuji K, Shigeta S, Tokunaga H, Kumada K, Komine K, Shirota H, Aoki Y, Motoike IN, Yasuda J, Kinoshita K, Yamamoto M, Koshiba S, Yaegashi N.
  • Journal Title: Toxins (Basel). Volume: 13(7) Pages: 461
  • DOI: 10.3390/toxins13070461.
  • Peer Reviewed / Open Access
• [Journal Article] CHD4 regulates platinum sensitivity through MDR1 expression in ovarian cancer: A potential role of CHD4 inhibition as a combination therapy with platinum agents. (2021)
  • Author(s): Oyama Y, Shigeta S, Tokunaga H, Tsuji K, Ishibashi M, Shibuya Y, Shimada M, Yasuda J, Yaegashi N.
  • Journal Title: PLoS One. Volume: 16(6) Pages: e0251079
  • DOI: 10.1371/journal.pone.0251079
  • Peer Reviewed / Open Access
• [Journal Article] Clinico-pathological characteristics of patients with stage IB1-IB2 (FIGO 2018) uterine cervical cancer: a nationwide study in Japan. (2021)
  • Author(s): Tsuji K, Shimada M, Takahashi F, Tokunaga H, Deura I, Yamaguchi S, Nakanishi T, Matsuo K, Yaegashi N, Mikami M.
  • Journal Title: Int J Clin Oncol. Volume: 26(8) Pages: 1541-1552
  • DOI: 10.1007/s10147-021-01938-4.
  • Peer Reviewed / Open Access
• [Journal Article] Establishment of a Diagnostic Method for Pelvic Sentinel Lymph Node Metastasis by Contrast-Enhanced Ultrasound in Uterine Cancer. (2021)
  • Author(s): Toki A, Niikura H, Mori N, Shigeta S, Nagai T, Tokunaga H, Shimada M, Yaegashi N.
  • Journal Title: Ultrasound Med Biol. Volume: 47(8) Pages: 2107-2116
  • DOI: 10.1016/j.ultrasmedbio.2021.03.040.
  • Peer Reviewed / Open Access
• [Journal Article] Prospective evaluation of sentinel node navigation surgery in Japanese patients with low-risk endometrial cancer-safety and occurrence of lymphedema. (2021)
  • Author(s): Niikura H, Toki A, Nagai T, Okamoto S, Shigeta S, Tokunaga H, Shimada M, Watanabe M, Yaegashi N.
  • Journal Title: Jpn J Clin Oncol Volume: 51(4) Pages: 584-589
  • DOI: 10.1093/jjco/hyaa252.
  • Peer Reviewed / Open Access
• [Journal Article] Association of subjective health and abnormal cervical cytology in Japanese pregnant women: An adjunct study of the Japan Environment and Children's Study. (2021)
  • Author(s): Sasaki S, Metoki H, Satoh M, Murakami T, Tanoue K, Tanaka K, Iwama N, Watanabe Z, Okamoto S, Saito M, Sugawara J, Ito K, Yaegashi N.
  • Journal Title: Prev Med Rep. Volume: 24 Pages: 101525
  • DOI: 10.1016/j.pmedr.2021.101525.
  • Peer Reviewed / Open Access
• [Journal Article] A Single Arm Prospective Pilot Study Examining the Efficacy and Safety of Bevacizumab Single Maintenance Therapy Following Platinum-Based Chemotherapy in Patients with Advanced or Recurrent Cervical Cancer. (2021)
  • Author(s): Toyoshima M, Shimada M, Sasaki S, Ishibashi M, Shigeta S, Tsuji K, Nagai T, Tokunaga H, Niikura H, Yaegashi N.
  • Journal Title: Tohoku J Exp Med. Volume: 254(3) Pages: 145-153
  • DOI: 10.1620/tjem.254.145.
  • Peer Reviewed / Open Access
• [Journal Article] The trend and outcome of postsurgical therapy for high-risk early-stage cervical cancer with lymph node metastasis in Japan: a report from the Japan Society of Gynecologic Oncology (JSGO) guidelines evaluation committee. (2021)
  • Author(s): Ikeda M, Shida M, Shigeta S, Nagase S, Takahashi F, Yamagami W, Katabuchi H, Yaegashi N, Aoki D, Mikami M.
  • Journal Title: J Gynecol Oncol. Volume: 32(3) Pages: e44
  • DOI: 10.3802/jgo.2021.32.e44.
  • Peer Reviewed / Open Access
• [Journal Article] A randomized phase II/III trial of conventional paclitaxel and carboplatin with or without bevacizumab versus dose-dense paclitaxel and carboplatin with or without bevacizumab, in stage IVB, recurrent, or persistent cervical carcinoma (JCOG1311): Primary analysis. (2021)
  • Author(s): Ishikawa M, Shibata T, Iwata T, Nishio S, Takada T, Suzuki S, Horie K, Kudaka W, Kagabu M, Tanikawa M, Kitagawa R, Takekuma M, Kobayashi H, Yaegashi N; Japan Clinical Oncology Group.
  • Journal Title: Gynecol Oncol. Volume: 162(2) Pages: 292-298
  • DOI: 10.1016/j.ygyno.2021.05.007.
  • Peer Reviewed / Open Access
• [Journal Article] Liquid biopsy with droplet digital PCR targeted to specific mutations in plasma cell-free tumor DNA can detect ovarian cancer recurrence earlier than CA125. (2021)
  • Author(s): Minato T, Ito S, Li B, Fujimori H, Mochizuki M, Yamaguchi K, Tamai K, Shimada M, Tokunaga H, Shigeta S, Sato I, Shima H, Yamada H, Yaegashi N, Yasuda J.
  • Journal Title: Gynecol Oncol Rep. Volume: 38 Pages: 100847
  • DOI: 10.1016/j.gore.2021.100847.
  • Peer Reviewed / Open Access
• [Journal Article] The Impact of Histological Subtype on Survival Outcome of Patients with Stage IIB-IVA Cervical Cancer Who Received Definitive Radiotherapy. (2021)
  • Author(s): Miyahara S, Tsuji K, Shimada M, Shibuya Y, Shigeta S, Nagai T, Umezawa R, Tokunaga H, Jingu K, Yaegashi N.
  • Journal Title: Tohoku J Exp Med. Volume: 255(4) Pages: 303-313
  • DOI: 10.1620/tjem.255.303.
  • Peer Reviewed / Open Access