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

2016 Fiscal Year Annual Research Report

• Project/Area Number: 26462721
• Research Institution: National Center for Child Health and Development
• Principal Investigator: 菱木 知郎 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
• Keywords: 神経芽腫 / 再発 / エクソーム解析

Outline of Annual Research Achievements

本研究次世代シークエンサーを用いた網羅的解析により神経芽腫が再発に至るメカニズムを解明することを目的とする。初発時および再発時の検体がセットで存在する神経芽腫症例につき、２点間のゲノム・エピゲノムレベルの変化を解析することによりクローン進化の機序を明白にし、神経芽腫が再発に至るプロセスで鍵となる分子の同定をめざす。
本年度は初発凍結検体、再発凍結検体及びコントロールとして末梢血DNAが揃った2症例にて前年度に検討した条件にて、それぞれエクソームシークエンスを実施した。１症例はMYCN増幅腫瘍であり残りの1症例はMYCN非増幅腫瘍である。このうちMYCN非増幅腫瘍にてCLC Genomics workbenchを用いて参照配列（hg19）にマッピングし体細胞変異解析を行った。初発検体では26遺伝子で再発検体では77遺伝子でアミノ酸置換を伴う体細胞遺伝子変異を見出し、17遺伝子が初発再発両腫瘍で共通していた。このうち初発の14遺伝子および再発の21遺伝子は以前に腫瘍で変異が報告されている遺伝子であった。これまでの報告から再発を呈する神経芽腫においてRAS-MAPKシグナルを活性化すると予測される遺伝子異常（ALK・NF1・PTPN11・FGFR1・NRAS・KRAS・HRAS ・BRAF）が見出されているが、本症例においてはこれら遺伝子に変異は生じていなかった。従って、この症例はRAS-MAPKシグナルを活性化とは異なるメカニズムによって治療抵抗性を獲得し再発に至ったと考えられる。

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 Pages: in press
  • DOI: 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 Pages: 122-131
  • DOI: 10.1016/S1470-2045(16)30598-8
  • Peer Reviewed / 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 Sci. Volume: 107 Pages: 812-819
  • DOI: 10.1111/cas.12928
  • Peer Reviewed
• [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 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 Sci. Volume: 107 Pages: 233-41
  • DOI: 10.1111/cas.12882.
  • Peer Reviewed
• [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. (2016)
  • 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: Eur J Cancer. Volume: 52 Pages: 92-101
  • DOI: 10.1016/j.ejca.2015.09.023
  • Peer Reviewed / Int'l Joint Research
• [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 – 2016-10-22
  • 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 – 2016-10-22
  • 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 – 2016-10-22
  • 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 – 2016-10-08
• [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 – 2016-06-23
  • 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 – 2016-06-23
  • 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 – 2016-06-23
  • Int'l Joint Research