Comprehensive genomic and transcriptome analyses to clarify molecular mechanisms contributing to chemoresistance in gynecologic cancer

• Project/Area Number: 19H03795
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56040:Obstetrics and gynecology-related
• Research Institution: Tohoku University
• Principal Investigator: YAEGASHI Nobuo 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
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000); Fiscal Year 2019: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 卵巣癌 / 薬剤耐性 / バイオマーカー / オミックス / メタボロミクス / 婦人科がん / がんゲノム解析 / メタボローム / 循環腫瘍DNA

Outline of Research at the Start

がん発症時のドライバー変異や治療標的候補分子の同定が進んでいるものの、がん薬物療法等により生じる遺伝子変異に基づく薬剤耐性獲得の分子機構は十分に解明されていない。一般に、再発あるいは残存腫瘍では外科的切除が困難な場合が多く、解析検体数が少ないが、婦人科がんの場合、再発・残存腫瘍に際し腹水穿刺や二次的手術等を選択することは少なくない。
本研究では再発ないし残存腫瘍のエキソーム解析やRNA-Seq解析等により耐性獲得の分子機構解明を進め、がん薬物療法等による治療戦略の再構築を目指す。研究期間の前半で薬剤耐性候補変異を探索し、後半では検証データによる仮説を立証する。

Outline of Final Research Achievements

We investigated the genomic alterations that potentially facilitate primary or acquired resistance to platinum agents in ovarian cancer by comprehensive genome analysis with surgically removed ovarian cancer specimens before and after chemotherapy. We found that KEAP1 mutation is possibly associated with chemoresistance in ovarian cancer. KEAP1 is known to repress the function of NRF2 which regulates chemosensitivity in variable cancer. Additional experiments are ongoing to validate the involvement of KEAP1 and NRF2 in chemoresistance of ovarian cancer.
In addition, approximately 600 metabolites in plasma from the patients with ovarian or endometrial cancer were measured to investigate the association between metabolomic status and chemosensitivity. We clarified several metabolomic profiles characteristic for ovarian and endometrial cancer, respectively. We also identified that increased tryptophan metabolism is significantly associated with chemoresistance in ovarian cancer.

Academic Significance and Societal Importance of the Research Achievements

進行再発卵巣がんでは白金製剤を中心とした抗がん剤治療が重要であり抗がん剤への耐性出現は治療における障壁となる。近年がんの遺伝子異常に応じた新しい治療が展開されているが卵巣がんの治療抵抗性にかかわる遺伝子異常の探索はこれまで十分になされていない。本研究は抗がん剤治療前後、あるいは治療抵抗性卵巣がん組織を応用することで新たに薬剤耐性に関わる遺伝子異常を発見した。さらに遺伝子異常以外に血液中の代謝産物の異常にも着目し、治療抵抗性に関与する代謝異常を同定した。これらは卵巣がんの薬剤耐性獲得の研究に大きく寄与するとともに、耐性克服を目指した新たな治療法の開発につながる結果である。

Research Products

• [Journal Article] Human papillomavirus vaccine effectiveness by age at first vaccination among Japanese women. (2022)
  • Author(s): Onuki M, Matsumoto K, et al. for The MINT Study Group.
  • Journal Title: Cancer Science Volume: 113 Issue: 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) Issue: 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, Matsumoto K, et al. for The Mint Study Group.
  • Journal Title: Vaccines (Basel) Volume: 10 Issue: 2 Pages: 181-181
  • DOI: 10.3390/vaccines10020188
  • Peer Reviewed / Open Access
• [Journal Article] Co-expression of nuclear heterogeneous nuclear ribonucleic protein K and estrogen receptor α in endometrial cancer (2022)
  • Author(s): Miki Yasuhiro、Iwabuchi Erina、Takagi Kiyoshi、Suzuki Takashi、Sasano Hironobu、Yaegashi Nobuo、Ito Kiyoshi
  • Journal Title: Pathology - Research and Practice Volume: 231 Pages: 153795-153795
  • 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: 24-35
  • 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) Issue: 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) Issue: 1
  • DOI: 10.3802/jgo.2022.33.e3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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 Issue: 9 Pages: 2039-2044
  • 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: The Tohoku Journal of Experimental Medicine Volume: 256 Issue: 3 Pages: 249-258
  • DOI: 10.1620/tjem.256.249
  • ISSN: 0040-8727, 1349-3329
  • 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) Issue: 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) Issue: 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) Issue: 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 Issue: 7 Pages: 461-461
  • DOI: 10.3390/toxins13070461
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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) Issue: 6 Pages: 0251079-0251079
  • 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) Issue: 8 Pages: 1541-1552
  • DOI: 10.1007/s10147-021-01938-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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) Issue: 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) Issue: 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: 101525-101525
  • 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) Issue: 3 Pages: 145-153
  • DOI: 10.1620/tjem.254.145
  • NAID: 130008061848
  • 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) Issue: 3
  • 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) Issue: 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: 100847-100847
  • 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: The Tohoku Journal of Experimental Medicine Volume: 255 Issue: 4 Pages: 303-313
  • DOI: 10.1620/tjem.255.303
  • NAID: 130008129404
  • ISSN: 0040-8727, 1349-3329
  • Peer Reviewed / Open Access
• [Journal Article] Novel candidates of pathogenic variants of the BRCA1 and BRCA2 genes from a dataset of 3,552 Japanese whole genomes (3.5KJPNv2) (2021)
  • Author(s): Tokunaga Hideki、Iida Keita、Hozawa Atsushi、Ogishima Soichi、Watanabe Yoh、Shigeta Shogo、Shimada Muneaki、Yamaguchi-Kabata Yumi、Tadaka Shu、Katsuoka Fumiki、Ito Shin、Kumada Kazuki、Hamanaka Yohei、Fuse Nobuo、Kinoshita Kengo、Yamamoto Masayuki、Yaegashi Nobuo、Yasuda Jun
  • Journal Title: PLOS ONE Volume: 16 Issue: 1 Pages: e0236907-e0236907
  • DOI: 10.1371/journal.pone.0236907
  • Peer Reviewed / Open Access
• [Journal Article] Robustness of a Cancer Profiling Test Using Formalin-fixed Paraffin Embedded Tumor Specimens (2021)
  • Author(s): ITO SHIN、SATO IKURO、MOCHIZUKI MAI、YAMAGUCHI KAZUNORI、TAMAI KEIICHI、MINATO TAKAMICHI、TANUMA NOBUHIRO、SHIMA HIROSHI、YASUDA JUN
  • Journal Title: Anticancer Research Volume: 41 Issue: 3 Pages: 1341-1348
  • DOI: 10.21873/anticanres.14891
  • Peer Reviewed / Open Access
• [Journal Article] A global phylogenetic analysis of Japanese tonsil-derived Epstein-Barr virus strains using viral whole-genome cloning and long-read sequencing (2021)
  • Author(s): Yajima Misako、Kakuta Risako、Saito Yutaro、Kitaya Shiori、Toyoda Atsushi、Ikuta Kazufumi、Yasuda Jun、Ohta Nobuo、Kanda Teru
  • Journal Title: Journal of General Virology Volume: 102 Issue: 3
  • DOI: 10.1099/jgv.0.001549
  • Peer Reviewed / Open Access
• [Journal Article] Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference (2021)
  • Author(s): Takayama Jun、Tadaka Shu、Yano Kenji、Katsuoka Fumiki、Gocho Chinatsu、Funayama Takamitsu、Makino Satoshi、Okamura Yasunobu、Kikuchi Atsuo、Sugimoto Sachiyo、Kawashima Junko、Otsuki Akihito、Sakurai-Yageta Mika、Yasuda Jun、Kure Shigeo、Kinoshita Kengo、Yamamoto Masayuki、Tamiya Gen
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 226-226
  • DOI: 10.1038/s41467-020-20146-8
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of a chemical compound that suppresses expression of BEX2, a dormant cancer stem cell-related protein (2021)
  • Author(s): Saijoh S, Nakamura-Shima M, Shibuya-Takahashi R, Ito R, Sugawara A, Yamazaki T, Imai T, Asada Y, Matsuura K, Iwai W, Wakui Y, Abue M, Kawamura S, Katayose Y, Fujimori H, Mochizuki M, Yasuda J, Yamaguchi K, Sugamura K,Satoh K, Katori Y, Tamai K.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 537 Pages: 132-139
  • DOI: 10.1016/j.bbrc.2020.11.022
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• [Journal Article] BEX2 suppresses mitochondrial activity and is required for dormant cancer stem cell maintenance in intrahepatic cholangiocarcinoma (2020)
  • Author(s): Tamai Keiichi、Nakamura-Shima Mao、Shibuya-Takahashi Rie、Kanno Shin-Ichiro、Yasui Akira、Mochizuki Mai、Iwai Wataru、Wakui Yuta、Abue Makoto、Yamamoto Kuniharu、Miura Koh、Mizuma Masamichi、Unno Michiaki、Kawamura Sadafumi、Sato Ikuro、Yasuda Jun、Yamaguchi Kazunori、Sugamura Kazuo、Satoh Kennichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 21592-21592
  • DOI: 10.1038/s41598-020-78539-0
  • Peer Reviewed / Open Access
• [Journal Article] Aberrant (pro)renin receptor expression induces genomic instability in pancreatic ductal adenocarcinoma through upregulation of SMARCA5/SNF2H (2020)
  • Author(s): Shibayama,Y., Takahashi, K., Yamaguchi, H., Yasuda, J., Yamazaki, D., Rahman, A., Fujimori, T., Fujisawa, Y., Takai, S., Furukawa, T., Nakagawa, T., Ohsaki, H., Kobara, H., Wong, J.H., Masaki, T., Yuzawa, Y., Kiyomoto, H., Yachida, S., Fujimoto, A., Nishiyama, A.
  • Journal Title: Communications Biology Volume: 3 Issue: 1 Pages: 724-724
  • DOI: 10.1038/s42003-020-01434-x
  • NAID: 130008001357
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of HLA-G long-read genomic sequences in mother?offspring pairs with preeclampsia (2020)
  • Author(s): Nishizawa Ayako、Kumada Kazuki、Tateno Keiko、Wagata Maiko、Saito Sakae、Katsuoka Fumiki、Mizuno Satoshi、Ogishima Soichi、Yamamoto Masayuki、Yasuda Jun、Sugawara Junichi
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 20027-20027
  • DOI: 10.1038/s41598-020-77081-3
  • Peer Reviewed / Open Access
• [Journal Article] Identification of the Novel Variants in Patients With Chronic Thromboembolic Pulmonary Hypertension (2020)
  • Author(s): Yaoita N, Satoh K, Tatebe S, Yasuda S, Shimokawa H et al.
  • Journal Title: J Am Heart Assoc . Volume: 9 Issue: 21 Pages: 1-12
  • DOI: 10.1161/jaha.120.015902
  • Peer Reviewed / Open Access