Unveiling the mechanism of recurrence and chemoresistance in neuroblastoma using genomewide and epigenomewide analysis

• Project/Area Number: 26462721
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatric surgery
• Research Institution: National Center for Child Health and Development (2016); Chiba Cancer Center (Research Institute) (2014-2015)
• Principal Investigator: Hishiki Tomoro 国立研究開発法人国立成育医療研究センター, 小児がんセンター, 医長 (00375776)
• Co-Investigator(Kenkyū-buntansha): 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, 研究所長 (90262708) ; 吉田 英生 千葉大学, 大学院医学研究院, 教授 (60210712)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 神経芽腫 / 再発 / 網羅的ゲノム解析 / 全エクソーム解析 / エクソーム解析 / 網羅的エピゲノム解析

Outline of Final Research Achievements

The prognosis of patients with high-risk neuroblastoma is extremely poor with a 5-year survival of 40%. Approximately 70% respond to chemotherapy but half of these patients experience recurrence. Once the tumor relapses, it gains chemoresistance and the outcome of relapsed patients is dismal. We hypothesized that tumors at diagnosis and recurrent tumors have different biological features based on different genomic and epigenetic rearrangements. We thus conducted a whole exome sequence for the tumors at diagnosis and tumors at recurrence in the identical patient. In one case, we found a novel somatic mutation in the recurrent tumor in a molecule that is not involved in the Ras-MAP kinase cascade, in which molecules has previously shown to be frequently mutated in recurrent tumors. This finding suggests that a somatic mutation in a molecule distinct from the Ras-MAPK cascade could also trigger relapse and chemoresistance in neuroblastoma.

Research Products

• [Journal Article] Genomic Analysis-Integrated Whole-exome Sequencing of Neuroblastomas Identifies Genetic Mutations in Axon Guidance Pathway. (2017)
  • Author(s): Yuanyuan Li, Miki Ohira, Yong Zhou, Teng Xiong, Wen Luo, Chao Yang, Xiangchun Li, Zhibo Gao, Yohko Nakamura, Takehiko Kamijo, Yasuhiko Kaneko, Takeshi Taketani, Junichi Ueyama, Tatsuro Tajiri, Hongyan Zhang, Jian Wang, Huanming Yang, Ye Yin, and Akira Nakagawara.
  • Journal Title: ONCOTARGET Volume: in press
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration. (2017)
  • Author(s): Meyers RL, Maibach R, Hiyama E, Harberle B, Krailo M, Rangaswami A, Aronson DC, Malogolowkin MH, Perilongo G, von Schweinitz D, Ansari M, Lopez-Terrada D, Tanaka Y, Alaggio R, Leuschner I, Hishiki T, Schmid I, Watanabe K, Yoshimura K, Feng Y, Rinaldi E, Saraceno D, Derosa M, Czauderna P.
  • Journal Title: Lancet Oncol. Volume: 18 Issue: 1 Pages: 122-131
  • DOI: 10.1016/s1470-2045(16)30598-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates (2016)
  • Author(s): Honda S, Minato M, Suzuki H, Fujiyoshi M, Miyagi H, Haruta M, Kaneko Y, Hatanaka KC, Hiyama E, Kamijo T, Okada T, Taketomi A
  • Journal Title: Cancer Science Volume: in press Issue: 6 Pages: 812-819
  • DOI: 10.1111/cas.12928
  • NAID: 120005828475
  • Peer Reviewed / Open Access
• [Journal Article] 分子生物学の新知見 (2016)
  • Author(s): 春田雅之,上條岳彦.
  • Journal Title: 小児外科 Volume: 48 Pages: 1129-113
• [Journal Article] Resectability and tumor response after preoperative chemotherapy in hepatoblastoma treated by the Japanese Study Group for Pediatric Liver Tumor (JPLT)-2 protocol. (2016)
  • Author(s): Hiyama E, Hishiki T, Watanabe K, Ida K, Yano M, Oue T, Iehara T, Hoshino K, Koh K, Tanaka Y, Kurihara S, Ueda Y, Onitake Y.
  • Journal Title: J Pediatr Surg. Volume: 51 Issue: 12 Pages: 2053-2057
  • DOI: 10.1016/j.jpedsurg.2016.09.038
  • Peer Reviewed
• [Journal Article] Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells. (2016)
  • Author(s): Mise N, Takami M, Suzuki A, Kamata T, Harada K, Hishiki T, Saito T, Terui K, Mitsunaga T, Nakata M, Ikeuchi T, Nakayama T, Yoshida H, Motohashi S
  • Journal Title: Cancer Science Volume: 107 Issue: 3 Pages: 233-241
  • DOI: 10.1111/cas.12882
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Children's Hepatic tumors International Collaboration (CHIC): Novel global rare tumor database yields new prognostic factors in hepatoblastoma and becomes a research model (2015)
  • Author(s): Czauderna P, Haeberle B, Hiyama E, Rangaswami A, Krailo M, Maibach R, Rinaldi E, Feng Y, Aronson D, Malogolowkin M, Yoshimura K, Leuschner I, Lopez-Terrada D, Hishiki T, Perilongo G, von Schweinitz D, Schmid I, Watanabe K, Derosa M, Meyers R
  • Journal Title: European Journal of Cancer Volume: 1 Pages: 92-101
  • DOI: 10.1016/j.ejca.2015.09.023
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correlation between the International Neuroblastoma Pathology Classification and genomic signature in neuroblastoma (2015)
  • Author(s): Nakazawa A, Haga C, Ohira M, Okita H, Kamijo T, Nakagawara A.
  • Journal Title: Cancer Sci. Volume: 未定 Issue: 6 Pages: 766-771
  • DOI: 10.1111/cas.12665
  • Peer Reviewed / Open Access
• [Journal Article] Oncolytic viral therapy for neuroblastoma cells with Sindbis virus AR339 strain. (2015)
  • Author(s): Takenouchi A, Saito K, Saito E, Saito T, Hishiki T, Matsunaga T, Isegawa N, Yoshida H, Ohnuma N, Shirasawa H.
  • Journal Title: Pediatr Surg Int. Volume: 31 Issue: 12 Pages: 1151-1159
  • DOI: 10.1007/s00383-015-3784-y
  • Peer Reviewed / Open Access
• [Journal Article] Radioguided localization of neuroblastomas in laparoscopic surgery using 123 I- radiolabeled metaiodobenzylguanidine (2015)
  • Author(s): Hishiki T, Saito T, Terui K, Mitsunaga T, Nakata M, Hayashi H, Yoshida H
  • Journal Title: Pediatric Blood & Cancer Volume: in press Issue: 7 Pages: 1297-1299
  • DOI: 10.1002/pbc.25488
  • Peer Reviewed / Open Access
• [Journal Article] Combination of carbon ion beam and gemcitabine causes irreparable DNA damage and death of radioresistant pancreatic cancer stem-like cells in vitro and in vivo. (2015)
  • Author(s): Sai S, Wakai T, Vares G, Yamada S, Kamijo T, Kamada T, Shirai T.
  • Journal Title: Oncotarget Volume: 6 Pages: 5517-35
  • Peer Reviewed
• [Journal Article] 小児固形腫瘍のがん幹細胞 (2015)
  • Author(s): 上條岳彦
  • Journal Title: 小児外科 Volume: 47 Pages: 123-128
  • Peer Reviewed
• [Journal Article] Radioguided localization of neuroblastomas in laparoscopic surgery using 123I- radiolabeled metaiodobenzylguanidine. (2015)
  • Author(s): Hishiki T, Saito T, Terui K, Mitsunaga T, Nakata M, Hayashi H, Yoshida H.
  • Journal Title: Pediatr Blood Cancer. Volume: 2015 Pages: 1297-1299
  • Peer Reviewed
• [Journal Article] Prognostic significance of Aminopeptidase-N (CD13) in hepatoblastoma (2015)
  • Author(s): Saida S, Watanabe KI, Kato I, Fujino H, Umeda K, Okamoto S, Uemoto S, Hishiki T, Yoshida H, Tanaka S, Adachi S, Niwa A, Nakahata T, Heike T
  • Journal Title: Pediatrics International Volume: in press Issue: 4 Pages: 558-566
  • DOI: 10.1111/ped.12597
  • Peer Reviewed
• [Journal Article] Malignant rhabdoid tumor of the liver: a case report and literature review. (2015)
  • Author(s): Oita S, Terui K, Komatsu S, Hishiki T, Saito T, Mitsunaga T, Nakata M, Yoshida H.
  • Journal Title: Pediatr Rep Volume: 7 Issue: 1 Pages: 5578-5578
  • DOI: 10.4081/pr.2015.5578
  • Peer Reviewed / Open Access
• [Journal Article] Unique expression features of cancer-type organic anion transporting polypeptide 1B3 mRNA expression in human colon and lung cancers: potential biomarker implications. (2014)
  • Author(s): Sun, Y., Furihata, T., Ishii, S., Nagai, M., Harada, M., Shimozato, O., Kamijo, T., Motohashi, S., Yoshino, I., Kamiichi, A., Kobayashi, K. and Chiba, K.
  • Journal Title: Clin. Transl. Med. Volume: 3 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s40169-014-0037-y
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-type protein tyrosine phosphatasedirectly dephosphorylates CD133 and regulates downstream AKT activation (2014)
  • Author(s): Shimozato O, Souda H
  • Journal Title: Oncogene Volume: 34(15) Issue: 15 Pages: 1-12
  • DOI: 10.1038/onc.2014.141
  • Peer Reviewed / Open Access
• [Journal Article] Histological features of primary tumors after induction or high-dose chemotherapy in high-risk neuroblastoma (2014)
  • Author(s): Hishiki T, Horie H, Higashimoto Y, Yotsumoto K, Komatsu S, Okimoto Y, Kakuda H, Taneyama Y, Saito T, Terui K, Mitsunaga T, Nakata M, Ochiai H, Hino M, Ando K, Yoshida H, Iwai J
  • Journal Title: Pediatric Surgery International Volume: 30 Issue: 9 Pages: 919-926
  • DOI: 10.1007/s00383-014-3564-0
  • Peer Reviewed
• [Journal Article] Coexistence of neuroblastoma detected on staging of Langerhans cell histiocytosis (2014)
  • Author(s): Shiohama T, Ochiai H, Hishiki T, Yoshida H, Kohno Y
  • Journal Title: Pediatrics International Volume: 56 Issue: 4 Pages: 608-610
  • DOI: 10.1111/ped.12292
  • Peer Reviewed
• [Presentation] 13.Trisomy 12 occurs before alteration of IGF2 expression and predicts favorable outcome in patients with Wilms tumors. (2016)
  • Author(s): Kaneko Y, Haruta M, Kamijo T, Arai Y, Okita H, Tanaka T, Takimoto H, Nakadate H, Oue T, Nozaki M, M Chin, Koshinaga T, Fukuzawa M.
  • Organizer: 48th Annual Congress of the International Society of Paediatric Oncology.
  • Place of Presentation: ダブリン
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] Surgical resectability and tumor response to preoperative chemotherapy in hepatoblastoma patients treated by the japanese study group for pediatric liver tumor (JPLT)-2 protocol. 48th congress of the international society of paediatric oncology. (2016)
  • Author(s): Hiyama E, Hishiki T, et al.
  • Organizer: 48th Annual Congress of the International Society of Paediatric Oncology.
  • Place of Presentation: ダブリン
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] Preoperative imaging and surgical outcome and morbidity in infants with retroperitoneal teratomas. (2016)
  • Author(s): Hishiki T et al
  • Organizer: 48th Annual Congress of the International Society of Paediatric Oncology.
  • Place of Presentation: ダブリン
  • Year and Date: 2016-10-19
  • Int'l Joint Research
• [Presentation] 4.神経芽腫幹細胞を制御する新規シグナル経路の解析 (2016)
  • Author(s): Miki Ohira, Koji Chikaraishi, Kyosuke Mukae, Nobuhiro Akita, Masayuki Haruta, Haruhiko Koseki, Takehiko Kamijo
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] CDX1 regulates cancer stemness pathway in neuroblastoma, CDX1 regulates cancer stemness pathway in neuroblastoma (2016)
  • Author(s): Hisanori Takenobu, Miki Ohira, Koji Chikaraishi, Nobuhiro Akita, Yohko Yamaguchi, Masayuki Haruta, Akira Nakagawara, Manabu Nakayama, Haruhiko Koseki, Takehiko Kamijo
  • Organizer: 国際神経芽腫学会 (ANR2016)
  • Place of Presentation: ケアンズ, オーストラリア
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Primary tumor resection after high dose chemotherapy with autologous hematopoietic stem cell transplantation is a safe and feasible option. A report from the Japanese neuroblastoma study group (JNBSG). (2016)
  • Author(s): 11.Hishiki T, Yoneda A, Kuroda T, Tokiwa K, Ise K, Ono S, Kinoshita Y, Uehara S, Matsumoto K, Kumagai M, Shichino H, Soejima T, Takimoto T, Hara J, Tajiri T, Nakagawara A.
  • Organizer: 国際神経芽腫学会 (ANR2016)
  • Place of Presentation: ケアンズ, オーストラリア
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] Phase I study of anti-GD2 antibody ch14.18/CHO long term infusion in recurrent or refractory neuroblastoma patients in Japan (2016)
  • Author(s): Atsushi Narita, Yoshiyuki Takahashi, Takehiko Kamijo, et al
  • Organizer: 国際神経芽腫学会 (ANR2016)
  • Place of Presentation: ケアンズ, オーストラリア
  • Year and Date: 2016-06-19
  • Int'l Joint Research
• [Presentation] 半定量的MIBGスコアによる転移性神経芽腫治療反応性の判定と初期反応不良例の臨床的生物学的特徴 (2014)
  • Author(s): Tomoro Hishiki, Yasuyuki Higashimoto, Katsumi Yotsumoto, Shugo Komatsu, Yuri Okimoto, Harumi Kakuda, Yuichi Taneyama, Kazuki Furudate, Takeshi Saito, Keita Terui, Tetsuya Mitsunaga, Mitsuyuki Nakata, Hidemasa Ochiai, Moeko Koshino, Kumiko Ando, Hideo Yoshida, and Jun Iwai
  • Organizer: 第52回日本小児血液・がん学会学術集会
  • Place of Presentation: 岡山市
  • Year and Date: 2014-11-28 – 2014-11-30
• [Presentation] TUMOR HISTOLOGY FOLLOWING INDUCTION CHEMOTHERAPY AND / OR HIGH-DOSE CHEMOTHERAPY AND ITS IMPACT ON THE OUTCOME OF PATIENTS WITH HIGH-RISK NEUROBLASTOMA (2014)
  • Author(s): Tomoro Hishiki, Hiroshi Horie, Yasuyuki Higashimoto, Katsumi Yotsumoto, Shugo Komatsu, Yuri Okimoto, Harumi Kakuda, Yuichi Taneyama, Takeshi Saito, Keita Terui, Tetsuya Mitsunaga, Mitsuyuki Nakata, Hidemasa Ochiai, Moeko Hino, Kumiko Ando, Hideo Yoshida, and Jun Iwai
  • Organizer: 46th annual congress of SIOP
  • Place of Presentation: トロント市（カナダ）
  • Year and Date: 2014-10-22 – 2014-10-25
• [Presentation] 進行神経芽腫原発巣的出時の 標本における病理組織像の検討 (2014)
  • Author(s): 菱木知郎、堀江 弘、東本恭幸、四本克己、小松秀吾、岩井潤 、吉田英生
  • Organizer: 第51回日本小児外科学会学術集会
  • Place of Presentation: 大阪市
  • Year and Date: 2014-05-08 – 2014-05-10
• [Book] 肝芽腫の診断と治療、「最新肝癌学」 (2014)
  • Author(s): 上條岳彦、檜山英三
  • Publisher: 日本臨牀社