Genomic and epigenomic profiling of high stage neuroblastoma

• Project/Area Number: 17K10131
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Research Institute for Clinical Oncology, Saitama Cancer Center
• Principal Investigator: Ohira Miki 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 主幹研究員 (20311384)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 神経芽腫 / ゲノム解析 / エピゲノム解析 / マイクロアレイ解析 / neuroblastoma

Outline of Final Research Achievements

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor with a wide range of clinical phenotypes. Although recent multidisciplinary treatment for NB improved patient outcomes, there still exists ultra-high-risk subset. In this study, meta-omics analysis of NB were performed to identify genomic signatures which characteraize high-risk type tumors. Target sequencing of high-risk NB cases registered in clinical studies and genome analysis of 92 ultra-high-risk NBs revealed certain genomic features characteristic in high-risk tumors. Based on these data, we designed a customized cancer gene panel which can survey gene alterations frequently observed in NB. In addition, from the 145 methylome data, several genomic regions which are highly methylated in high-risk NB were selected. The pediatric cancer panel and methylome markers will provide beneficial information for considering a subsequent therapeutic strategies for high-risk NBs.

Academic Significance and Societal Importance of the Research Achievements

本研究で得られたデータは、今後国際神経芽腫リスクグループ（INRG）が構築している神経芽腫リスク分類データベース(iINRGdb)と共有し、国内外での関連領域の研究や臨床への還元に活用される予定である。また、小児がんに特化したがん遺伝子パネルは神経芽腫のがんゲノム医療に貢献するものと期待される。

Research Products

• [Journal Article] TAp63 represses transcription of MYCN/NCYM gene and its high levels of expression are associated with favorable outcome in neuroblastoma (2019)
  • Author(s): Suenaga Yusuke、Yamamoto Mami、Sakuma Tetsushi、Sasada Manabu、Fukai Fumio、Ohira Miki、Yamaguchi Yohko、Yamamoto Takashi、Ando Kiyohiro、Ozaki Toshinori、Nakagawara Akira
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 518 Issue: 2 Pages: 311-318
  • DOI: 10.1016/j.bbrc.2019.08.052
  • Peer Reviewed
• [Journal Article] Genomic Amplifications and Distal 6q Loss: Novel Markers for Poor Survival in High-risk Neuroblastoma Patients (2018)
  • Author(s): Depuydt P、Boeva V、Hocking TD、Cannoodt R、Ambros IM、Ambros PF、Asgharzadeh S、Attiyeh EF、Combaret V、Defferrari R、Fischer M、Hero B、Hogarty M、Irwin MS、Koster J、Kreissman S、Ladenstein R、Lapouble E、Laureys G、London WB、Mazzocco K、Nakagawara A、Noguera R、Ohira M、Park JR、Potschger U、Theissen J、et al
  • Journal Title: JNCI: Journal of the National Cancer Institute Volume: 110 Issue: 10 Pages: 1084-1093
  • DOI: 10.1093/jnci/djy022
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG) (2018)
  • Author(s): Hishiki T、For the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)、Matsumoto K、Ohira M、Kamijo T、Shichino H、Kuroda T、Yoneda A、Soejima T、Nakazawa A、Takimoto T、Yokota I、Teramukai S、Takahashi H、Fukushima T、Kaneko T、Hara J、Kaneko M、Ikeda H、Tajiri T、Nakagawara A
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 5 Pages: 965-973
  • DOI: 10.1007/s10147-018-1281-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] PPP3CB contributes to poor prognosis through activating nuclear factor of activated T-cells signaling in neuroblastoma (2018)
  • Author(s): Shakhova Irina、Li Yuanyuan、Yu Fan、Kaneko Yoshiki、Nakamura Yohko、Ohira Miki、Izumi Hideki、Mae Takao、Varfolomeeva Svetlana R.、Rumyantsev Alexander G.、Nakagawara Akira
  • Journal Title: Molecular Carcinogenesis Volume: 58 Issue: 3 Pages: 426-435
  • DOI: 10.1002/mc.22939
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications (2018)
  • Author(s): Li Zhenghao、Takenobu Hisanori、Setyawati Amallia Nuggetsiana、Akita Nobuhiro、Haruta Masayuki、Satoh Shunpei、Shinno Yoshitaka、Chikaraishi Koji、Mukae Kyosuke、Akter Jesmin、Sugino Ryuichi P.、Nakazawa Atsuko、Nakagawara Akira、Aburatani Hiroyuki、Ohira Miki、Kamijo Takehiko
  • Journal Title: Oncogene Volume: 37 Issue: 20 Pages: 2714-2727
  • DOI: 10.1038/s41388-018-0133-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): 1.Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106296-106310
  • DOI: 10.18632/oncotarget.22435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis (2017)
  • Author(s): Uryu K, Nishimura R, Kataoka K, Sato Y, Nakazawa A, Suzuki H, Yoshida K, Seki M, Hiwatari M, Isobe T, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Koh K, Hanada R, Oka A, Hayashi Y, Ohira M, Kamijo T, Nagase H, Takimoto T, Tajiri T, Nakagawara A, Ogawa S, Takita J
  • Journal Title: Oncotarget Volume: 8 Issue: 64 Pages: 107513-107529
  • DOI: 10.18632/oncotarget.22495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of DNA Damage Response in Neuroblastoma and Utility of a PARP Inhibitor. (2017)
  • Author(s): Takagi M, Yoshida M, Nemoto Y, Tamaichi H, Tsuchida R, Seki M, Uryu K, Nishii R, Miyamoto S, Saito M, Hanada R, Kaneko H, Miyano S, Kataoka K, Yoshida K, Ohira M, Hayashi Y, Nakagawara A, Ogawa S, Mizutani S, Takita J.
  • Journal Title: J Natl Cancer Inst. Volume: 1;109(11) Issue: 11 Pages: 1-12
  • DOI: 10.1093/jnci/djx062
  • Peer Reviewed / Open Access
• [Journal Article] PRC2-Mediated Transcriptomic Alterations at the Embryonic Stage Govern Tumorigenesis and Clinical Outcome in MYCN-Driven Neuroblastoma (2017)
  • Author(s): 2.Tsubota S, Kishida S, Shimamura T, Ohira M, Yamashita S, Cao D, Kiyonari S, Ushijima T, Kadomatsu K.
  • Journal Title: Cancer Res. Volume: 77 Issue: 19 Pages: 5259-5271
  • DOI: 10.1158/0008-5472.can-16-3144
  • Peer Reviewed
• [Journal Article] CFC1 is a cancer stemness-regulating factor in neuroblastoma (2017)
  • Author(s): Chikaraishi Koji、Takenobu Hisanori、Sugino Ryuichi P.、Mukae Kyosuke、Akter Jesmin、Haruta Masayuki、Kurosumi Masafumi、Endo Takaho A.、Koseki Haruhiko、Shimojo Naoki、Ohira Miki、Kamijo Takehiko
  • Journal Title: Oncotarget Volume: 8 Issue: 28 Pages: 45046-45059
  • DOI: 10.18632/oncotarget.18464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic analysis–integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway (2017)
  • Author(s): Li Yuanyuan、Ohira Miki、Zhou Yong、Xiong Teng、Luo Wen、Yang Chao、Li Xiangchun、Gao Zhibo、Zhou Rui、Nakamura Yohko、Kamijo Takehiko、Kaneko Yasuhiko、Taketani Takeshi、Ueyama Junichi、Tajiri Tatsuro、Zhang Hongyan、Wang Jian、Yang Huanming、Yin Ye、Nakagawara Akira
  • Journal Title: Oncotarget Volume: 8 Issue: 34 Pages: 56684-56697
  • DOI: 10.18632/oncotarget.18079
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 高リスク神経芽腫のがん遺伝子パネル解析 (2019)
  • Author(s): 大平美紀、七野博之、久保崇、春田雅之、瀧本哲也、中澤温子、山崎文登、永瀬浩喜、田尻達郎、中川原章、市川仁、菱木知郎、上條岳彦
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] 高リスク神経芽腫のゲノム医療構築を目的としたがん遺伝子パネル解析 (2019)
  • Author(s): 大平美紀、七野博之、久保崇、春田雅之、瀧本哲也、中澤温子、山崎文登、永瀬浩喜、田尻達郎、中川原章、市川仁、菱木知郎、上條岳彦
  • Organizer: 第61回日本小児血液・がん学会学術集会
• [Presentation] Genomic and epigenome profiling of high stage neuroblastoma (2018)
  • Author(s): 大平美紀 杉野隆一 竹信尚典 李正皓 春田雅之 上條岳彦 他4名
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Genomic characterization of high-risk/ultra-high-risk neuroblastomas found in 610 patients registered in Japan Children’s Study Group (JCCG) Neuroblastoma Committee (JNBSG) (2018)
  • Author(s): 大平美紀 上條岳彦 杉野隆一 春田雅之 竹信尚典 他14名
  • Organizer: Advances in Neuroblastoma Research 2018 (ANR2018)
  • Int'l Joint Research
• [Presentation] 進行神経芽腫の次世代型網羅的ゲノム・エピゲノム解析：小児がんゲノム医療への応用を目指して (2018)
  • Author(s): 大平美紀
  • Organizer: 第38回日本小児病理研究会学術集会
  • Invited
• [Presentation] Genomic characterization of ultra-high-risk neuroblastoma (2018)
  • Author(s): 大平美紀 杉野隆一 春田雅之 竹信尚典 上條岳彦 他7名
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 超高リスク神経芽腫のゲノム解析 (2018)
  • Author(s): 大平美紀 杉野隆一 春田雅之 竹信尚典 上條岳彦 他13名
  • Organizer: 第60回日本小児血液・がん学会学術集会
• [Presentation] Genomic and epigenomic profiling of high stage neuroblastoma (2017)
  • Author(s): 大平美紀 杉野隆一 上條岳彦 他10名
  • Organizer: AACR Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] ゲノム・エピゲノム異常を用いた神経芽腫の新規リスク分類―JCCG-JNBSG高リスク臨床試験登録例の解析 (2017)
  • Author(s): 大平美紀 上條岳彦 他10名
  • Organizer: 第76回日本癌学会学術総会
• [Presentation] Genome-based molecular diagnosis of neuroblastoma (2017)
  • Author(s): 大平美紀
  • Organizer: 2017 Asia-Pacific Symposium of Neuroblastoma
  • Int'l Joint Research
• [Presentation] Genome-based risk stratification of neuroblastoma and Wilms tumor: Toward clinical application of precision medicine (2017)
  • Author(s): 大平美紀 春田雅之 金子安比古 上條岳彦 他1名
  • Organizer: 第59回日本小児血液・がん学会学術集会