Development for a new histobiological risk stratification and establishing of genomic medicine for pediatric malignant solid tumors

2020 Fiscal Year Annual Research Report

• Project/Area Number: 17H01592
• Research Institution: Chiba University
• Principal Investigator: 菱木 知郎 千葉大学, 大学院医学研究院, 教授 (00375776)
• Co-Investigator(Kenkyū-buntansha): 市川 仁 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (30201924) ; 上條 岳彦 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 所長 (90262708) ; 瀧本 哲也 国立研究開発法人国立成育医療研究センター, 研究所小児がん疫学臨床研究センター, 室長 (40393178)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Keywords: 小児がん / 神経芽腫 / 遺伝子パネル / ゲノム医療

Outline of Annual Research Achievements

本研究で開発したNCC Oncopanel Ped検査（保険収載がん遺伝子パネル検査NCC Oncopanelに小児がんにおいて治療標的／予後因子となる遺伝子と生殖細胞系列変異が知られる遺伝子を追加したもの）の臨床的実行性・有用性の評価を行った。読み取り深度の均一性を高めたNCC Oncopanel Ped v1.1を品質保証下で稼働させる体制を2019年度に構築し、国立がん研究センター中央病院で行われている前向き臨床研究「TOP-GEAR」において、新たに24例（2019年度実施分と合わせて計35例）の小児がん患者に対し本検査を実施した。臨床現場において十分稼働可能であることが確認されるとともに、VEGFA増幅、ATRX欠失などの追加遺伝子のactionable異常が検出され、本パネル検査の保険収載検査に対する優位性も示された。しかし、その優位性が限定的であったため、本パネル自体の臨床開発は断念する判断を行った。一方、NTRK3融合遺伝子検出能などの一部機能については、NCC Oncopanelの改良（一部変更申請）に活かされることになった。
また、高リスク神経芽腫試験JN-H-11の登録例50例について後方視的に解析を行った。9割にあたる45例に１つ以上の変異が検出され、テロメラーゼ上流域のゲノム再編成の検出については限定的であったものの、コピーナンバー異常の検出による腫瘍のゲノムグループ分類も可能であることが示された。今回エビデンスレベルC,Dにあたる変異が少なくとも１割強にあたる６例に検出され、治療感受性マーカーに関する情報も得られた。（エビデンスレベルは３学会合同ガイダンスv2.1に従った。）本パネルを用いた小児がん関連遺伝子の異常と、別途テロメア維持機構スクリーニング法を組み合わせることで、神経芽腫のリスク分類に有用な情報が得られることが示された。

Research Progress Status

令和2年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和2年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] CEP131 Abrogates CHK1 Inhibitor-Induced Replication Defects and Is Associated with Unfavorable Outcome in Neuroblastoma. (2020)
  • Author(s): Ando K, Cazares-Ordonez V, Makishima M, Yokoyama A, Suenaga Y, Nagase H, Kobayashi S, Kamijo T, Koshinaga T, Wada S.
  • Journal Title: J Oncol. Volume: 電子 Pages: 2752417
  • DOI: 10.1155/2020/2752417
  • Peer Reviewed / Open Access
• [Journal Article] RING1A regulates RING1B expression and the collapse of its expression impairs neuroblastoma cell proliferation (2020)
  • Author(s): Hasegawa M, Satoi S, Kamijo T
  • Journal Title: Dokkyo Journal of Medical Sciences Volume: 47 Pages: 115-123
  • Peer Reviewed
• [Journal Article] A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project. (2020)
  • Author(s): Moreno L, Guo D, Irwin MS, Berthold F, Hogarty M, Kamijo T, Morgenstern D, Pasqualini C, Ash S, Potschger U, Ladenstein R, Valteau-Couanet D, Cohn SL, Pearson ADJ, London WB.
  • Journal Title: Pediatr Blood Cancer Volume: 電子 Pages: e28794
  • DOI: 10.1002/pbc.28794.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. (2020)
  • Author(s): Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, et al
  • Journal Title: N Engl J Med Volume: 384 Pages: 42-50
  • DOI: 10.1056/NEJMoa2030391.
  • Peer Reviewed
• [Journal Article] BRAF V600E mutation is a potential therapeutic target for a small subset of synovial sarcoma (2020)
  • Author(s): Watanabe Sho、Shimomura Akihiko、Kubo Takashi、Sekimizu Masaya、Seo Takuji、Watanabe Shun-Ichi、Kawai Akira、Yamamoto Noboru、Tamura Kenji、Kohno Takashi、Ichikawa Hitoshi、Yoshida Akihiko
  • Journal Title: Modern Pathology Volume: 33 Pages: 1660～1668
  • DOI: 10.1038/s41379-020-0530-3
  • Peer Reviewed
• [Journal Article] Sindbis viral structural protein cytotoxicity on human neuroblastoma cells. (2020)
  • Author(s): Saito EY, Saito K, Hishiki T, Takenouchi A, Saito T, Sato Y, Terui K, Matsunaga T, Shirasawa H, Yoshida H.
  • Journal Title: Pediatr Surg Int Volume: 36 Pages: 1173-1180
  • DOI: 10.1007/s00383-020-04719-8
  • Peer Reviewed
• [Journal Article] Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol. (2020)
  • Author(s): Hiyama E, Hishiki T, Watanabe K, Ida K, Ueda Y, Kurihara S, Yano M, Hoshino K, Yokoi A, Takama Y, Nogami Y, Taguchi T, Mori M, Kihira K, Miyazaki O, Fuji H, Honda S, Iehara T, Kazama T, Fujimura J, Tanaka Y, Inoue T, Tajiri T, Kondo S, Oue T, Yoshimura K.
  • Journal Title: J Clin Oncol. Volume: 38 Pages: 2488-2498.
  • DOI: 10.1200/JCO.19.01067.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database (2020)
  • Author(s): Haeberle B, Rangaswami A, Krailo M, Czauderna P, Hiyama E, Maibach R, Lopez-Terrada D, Aronson DC, Alaggio R, Ansari M, Malogolowkin MH, Perilongo G, O'Neill AF, Trobaugh-Lotrario AD, Watanabe K, Schmid I, von Schweinitz D, Ranganathan S, Yoshimura K, Hishiki T, et al
  • Journal Title: Pediatric Blood & Cancer Volume: 67 Pages: e28350
  • DOI: 10.1002/pbc.28350
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] High prevalence of SMARCB1 constitutional abnormalities including mosaicism in malignant rhabdoid tumors. (2020)
  • Author(s): Shirai R, Osumi T, Terashima K, Kiyotani C, Uchiyama M, Tsujimoto S, Yoshida M, Yoshida K, Uchiyama T, Tomizawa D, Shioda Y, Sekiguchi M, Watanabe K, Keino D, Ueno-Yokohata H, Ohki K, Takita J, Ito S, Deguchi T, Kiyokawa N, Ogiwara H, Hishiki T, Ogawa S, Okita H, Matsumoto K, Yoshioka T, Kato M.
  • Journal Title: Eur J Hum Genet. Volume: 28 Pages: 1124-1128
  • DOI: 10.1038/s41431-020-0614-z
  • Peer Reviewed
• [Journal Article] Definitive Tumor Resection after Myeloablative High Dose Chemotherapy Is a Feasible and Effective Option in the Multimodal Treatment of High-Risk Neuroblastoma: A Single Institution Experience. (2020)
  • Author(s): Hishiki T, Fujino A, Watanabe T, Tahara K, Ohno M, Yamada Y, Tomonaga K, Kutsukake M, Fujita T, Kawakubo N, Matsumoto K, Kiyotani C, Shioda Y, Miyazaki O, Fuji H, Yoshioka T, Kanamori Y.
  • Journal Title: J Pediatr Surg. Volume: 55 Pages: 1655-1659.
  • DOI: 10.1016/j.jpedsurg.2019.08.050.
  • Peer Reviewed
• [Journal Article] Prospective Study of Allogeneic Hematopoietic Stem Cell Transplantation with Post-Transplantation Cyclophosphamide and Antithymocyte Globulin from HLA-Mismatched Related Donors for Nonmalignant Diseases. (2020)
  • Author(s): Osumi T, Yoshimura S, Sako M, Uchiyama T, Ishikawa T, Kawai T, Inoue E, Takimoto T, Takeuchi I, Yamada M, Sakamoto K, Yoshida K, Kimura Y, Matsukawa Y, Matsumoto K, Imadome KI, Arai K, Deguchi T, Imai K, Yuza Y, Matsumoto K, Onodera M, Kanegane H, Tomizawa D, Kato M
  • Journal Title: Biol Blood Marrow Transplant Volume: 26 Pages: e286-e291.
  • DOI: 10.1016/j.bbmt.2020.08.008.
  • Peer Reviewed
• [Journal Article] A phase II JN-I-10 efficacy study of IDRF-based surgical decisions and stepwise treatment intensification for patients with intermediate-risk neuroblastoma: a study protocol. (2020)
  • Author(s): Iehara T, Yoneda A, Kikuta A, Muraji T, Tokiwa K, Takahashi H, Teramukai S, Takimoto T, Yagyu S, Hosoi H, Tajiri T
  • Journal Title: BMC Pediatr. Volume: 20 Pages: 212
  • DOI: 10.1186/s12887-020-02061-5.
• [Presentation] FGFR2はMEK/ERK signalingを介してCHK1阻害剤感受性を低下せしめる (2021)
  • Author(s): 安藤清宏、大平美紀、末永祐介、上條岳彦、永瀬浩喜、小林真一、和田聡
  • Organizer: 第29回日本癌病態治療研究会
• [Presentation] NCC Oncopanel Ped: A novel cancer gene panel test for pediatric solid tumors (2020)
  • Author(s): Fumito Yamazaki, Takashi Kubo, Kuniko Sunami, Takafumi Koyama, Ayumu Arakawa, Sachiyo Mitani, Miki Ohira, Motohiro Kato, Atsuko Nakazawa, Takashi Kohno, Noboru Yamamoto, Takehiko Kamijo, Tomoro Hishiki, Chitose Ogawa, Hitoshi Ichikawa：
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Mutational profiling and copy number analysis suggest homologous recombination deficiency in osteosarcoma (2020)
  • Author(s): Fumito Yamazaki, Naofumi Asano, Masaya Sekimizu, Sachiyo Mitani, Takashi Kubo, Chitose Ogawa, Akira Kawai, Akihiko Yoshida, Hitoshi Ichikawa
  • Organizer: 第62回日本小児血液・がん学会学術集会
• [Presentation] Polycomb repressive complex 1 controls a tumor suppressor gene BTG2 in neuroblastoma. (2020)
  • Author(s): Shunpei Satoh, Mariko Hasegawa, Miki Ohira, Takehiko Kamijo
  • Organizer: 2020APSN
• [Presentation] Genomic characterization of high-risk neuroblastoma by cancer gene panel test (2020)
  • Author(s): Miki Ohira, Hiroyuki Shichino, Takashi Kubo, Masayuki Haruta, Tetsuya Takimoto, Atsuko Nakazawa, Fumito Yamazaki, Hiroki Nagase, Tatsuro Tajiri, Akira Nakagawara, Hitoshi Ichikawa, Tomoro Hishiki, Takehiko Kamijo
  • Organizer: 2020APSN
• [Presentation] 神経芽腫における分化関連遺伝子のエピジェネティックな発現抑制メカニズムの解明 (2020)
  • Author(s): Hisanori Takenobu, Zhenghao Li, Ryuichi P. Sugino, Kyosuke Mukae, Miki Ohira, Masayuki Haruta, Yuki Endo, Ryu Okada, Dilibaerguli Shaliman, Takehiko Kamijo
  • Organizer: 2020 エピジェネティック研究会
• [Presentation] 神経芽腫におけるＥＺＨ２特異的阻害剤の感受性を制御する分子の探索 (2020)
  • Author(s): 遠藤悠紀、 竹信尚典、仁尾正記、上條岳彦
  • Organizer: 第57回日本小児外科学会学術集会
• [Presentation] Development of artificial tumorigenesis model from iPSC-based neural crest cells (2020)
  • Author(s): Kyosuke Mukae, Hisanori Takenobu, Hiroaki Kanda, Miki Ohira, Yuki Endo, Masayuki Haruta, Junya Toguchida, Kenji Osafune, Tatsutoshi Nakahata, Takehiko Kamijo
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] Q-PCR C-circle assay may be useful to identify NB patients with poorer prognosis in each High and Low/Intermediate risk. (2020)
  • Author(s): Motoki Sugawara, Masayuki Haruta, Atsuko Nakazawa, Hajime Okita, Tetsuya Takimoto, Tatsuro Tajiri, Shuichiro Uehara, Tsugumichi Koshinaga, Miki Ohira, Takehiko Kamijo,
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] Genomic characterization of high-risk neuroblastoma by cancer gene panel tests (2020)
  • Author(s): Miki Ohira, Hiroyuki Shichino, Takashi Kubo, Masayuki Haruta, Tetsuya Takimoto, Atsuko Nakazawa, Fumito Yamazaki, Hiroki Nagase, Tatsuro Tajiri, Akira Nakagawara, Hitoshi Ichikawa, Tomoro Hishiki, Takehiko Kamijo
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] Evaluation of the treatment results according to the status between renal vessels and tumor in the low-risk patients with abdominal neuroblastoma; analysys of the patients who enrolled in the low-risk protocol (JN-L-10) from the japan children’s cancer group neuroblastoma committee (2020)
  • Author(s): Yoneda A , Iehara T, Yokota I , Takahashi H , Teramukai S, Kamijo T, Nakazawa A, Takimoto T, Kikuta A , Ikeda H, Nakagawara A, Tajiri T
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] A polycomb group protein RING1A preferentially mediates H2AK119 ubiquitination with supporting neuroblastoma cell proliferation. (2020)
  • Author(s): Shunpei Satoh1, Mariko Hasegawa1, 2, Miki Ohira1, Hitoshi Ikeda2, Takehiko Kamijo
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] Delayed local treatment and Busulfan/Melphalan as a myeloablative chemotherapy for high-risk neuroblastoma (JN-H-15): a report from Neuroblastoma Committee of Japan Children’s Cancer Group (JCCG) Trial (2020)
  • Author(s): Matsumoto, Kimikazu, Shichino, Hiroyuki, Yoneda, Akihiro, Hishiki, Tomoro, et al
  • Organizer: 第 62 回日本小児血液・がん学会学術集会
• [Presentation] Genomic characterization of high-risk neuroblastoma by NCC Oncopanel Ped cancer panel (2020)
  • Author(s): Miki Ohira (1), Hiroyuki Shichino (2), Takashi Kubo (3), Masayuki Haruta (1), Tetsuya Takimoto (4), Atsuko Nakazawa (5), Fumito Yamazaki (3), Hiroki Nagase (6), Tatsuro Tajiri (7), Akira Nakagawara (8), Hitoshi Ichikawa (3), Tomoro Hishiki (4), Takehiko Kamijo (1),
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] p53 deficiency limits ATRX loss induced replication stress and genome instability in neuroblastoma cells (2020)
  • Author(s): Jesmin Akter1, Parvin Sultana1,2, Hisanori Takenobu1, Miki Ohira1, Ryuichi Sugino1, Masayuki Haruta1, and Takehiko Kamijo1
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Tumor sphere specific gene CDX1 binds to OCT4 and MAX promoters to regulates stemness (2020)
  • Author(s): Hisanori Takenobu, Miki Ohira, Ryuichi Sugino, Koji Chikaraishi, Ryu Okada, Kyosuke Mukae, Tomoko Wada, Yuki Endo, Nobuhiro Akita, Masayuki Haruta, Takehiko Kamijo
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] Recurrent breakpoints in 22q11 segmental duplication regions reveal distinct tumorigenesis in rhabdoid tumor of kidney (2020)
  • Author(s): Kaneko Yasuhiko, Haruta Masayuki, Arai Yasuhito, Sugino Ryuichi, Kamijo Takehiko, Okita Hajime, Oue Takaharu, Koshinaga Tsugumichi
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 神経芽腫細胞における紫外線不活化シンドビスウイルスの抗腫瘍効果 (2020)
  • Author(s): 大野 吉史, 齋藤 謙悟, 李 斉森, 馬 雪, 齋藤 江里子, 室山 良介, 菱木 知郎, 白澤 浩
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] ゲノム医療:小児・AYAがんにおける実装の現状と今後の課題 小児がんゲノム検査の今後の展望 (2020)
  • Author(s): 菱木知郎
  • Organizer: 第62回日本小児血液・がん学会学術集会