Comprehensive genome analysis of aggressive neuroblastoma

• Project/Area Number: 23591562
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Chiba Cancer Center (Research Institute)
• Principal Investigator: OHIRA Miki 千葉県がんセンター(研究所), がんゲノム研究室, 室長 (20311384)
• Co-Investigator(Renkei-kenkyūsha): NAKAGAWARA Akira 千葉県がんセンター, 病院長 (50117181)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2011: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 癌 / 神経芽腫 / マイクロアレイ / 遺伝子 / ゲノム

Research Abstract

Neuroblastoma is one of the most common cancer in children, and is known to exhibit wide ranges of clinical behavior, from spontaneous regression to highly resistant to chemotherapy. In this study, to construct better therapeutic strategies for each tumor subtype, we conducted integrated molecular profiling to find genome copy number aberrations, mRNA/miRNA expression patterns as well as epigenetic changes occurred frequently in aggressive neuroblastomas. A set of markers we found showed significant correlations with patient prognoses and could add new insights to develop a novel diagnostic system or to select suitable clinical treatment by using them.

Research Products

• [Journal Article] Novel 1p tumour suppressor Dnmt1-associated protein 1 regulates MYCN/ataxia telangiectasia mutated/p53 pathway (2014)
  • Author(s): Yamaguchi Y, Takenobu H, Ohir a M, Nakazawa A, Yoshida S, Akita N, Shimozato O, Iwama A, Nakagawara A, Kamijo T.
  • Journal Title: Eur J Cancer Volume: 50 Pages: 1555-1565
  • Peer Reviewed
• [Journal Article] NCYM, a Cis-antisense gene of MYCN, encodes a de novo evolved protein that inhibits GSK3β resulting in the stabilization of MYCN in human neuroblastomas. (2014)
  • Author(s): Suenaga Y, Islam SM, Alagu J, Kaneko Y, Kato M, Tanaka Y, Kawana H, Hossain S, Matsumoto D, Yamamoto M, Shoji W, Itami M, Shibata T, Nakamura Y, Ohira M, Haraguchi S, Takatori A, Nakagawara A.
  • Journal Title: PLoS Genet Volume: 10 Issue: 1 Pages: 1-14
  • DOI: 10.1371/journal.pgen.1003996
  • Peer Reviewed / Open Access
• [Journal Article] ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma. (2013)
  • Author(s): Hasan MK, Nafady A, Takatori A, Kishida S, Ohira M, Suenaga Y, Hossain S, Akter J, Ogura A, Nakamura Y, Kadomatsu K, Nakagawara A.
  • Journal Title: Sci Rep Volume: 3 Issue: 1 Pages: 3450-3450
  • DOI: 10.1038/srep03450
  • Peer Reviewed
• [Journal Article] RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma (2013)
  • Author(s): Yu F, Gao W, Yokochi T, Suenaga Y, Ando K, Ohir a M, Nakamura Y, Nakagawara A.
  • Journal Title: Oncogene Volume: 33 Pages: 2601-2609
  • Peer Reviewed
• [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression (2013)
  • Author(s): Zhu Y, Li Y, Haraguchi S, Yu M, Ohir a M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
  • Journal Title: J Clin Invest Volume: 123 Pages: 2935-2947
  • Peer Reviewed
• [Journal Article] Stronger prognostic power of the CpG island methylator phenotype than methylation of individual genes in neuroblastomas (2013)
  • Author(s): Asada K, Watanabe N, Nakamura Y, Ohir a M, Westermann F, Schwab M, Nakagawara A, Ushijima T.
  • Journal Title: J pn J Clin Oncol Volume: 43 Pages: 641-645
  • Peer Reviewed
• [Journal Article] Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma (2013)
  • Author(s): Takagi D, Tatsumi Y, Yokochi T, Takatori A, Ohir a M, Kamijo T, Kondo S, Fujii Y, Nakagawara A.
  • Journal Title: Cancer Sci Volume: 104 Pages: 563-572
  • Peer Reviewed
• [Journal Article] A MYCN-amplified cell line derived from a long-term event-free survivor among our sixteen established neuroblastoma cell lines (2013)
  • Author(s): Sugimoto T, Gotoh T, Yagyu S, Kuroda H, Iehara T, Hosoi H, Ohta S, Ohir a M, Nakagawara A.
  • Journal Title: Cancer Lett Volume: 331 Pages: 115-121
  • Peer Reviewed
• [Journal Article] Temozolomide suppresses MYC via activation of TAp63 to inhibit progression of human glioblastoma. (2013)
  • Author(s): Yamaki T, Suenaga Y, Iuchi T, Alagu J, Takatori A, Itami M, Araki A, Ohira M, Inoue M, Kageyama H, Yokoi S, Saeki N, Nakagawara A.
  • Journal Title: Sci Rep. Volume: 3 Issue: 1 Pages: 1160-1160
  • DOI: 10.1038/srep01160
  • Peer Reviewed
• [Journal Article] Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma (2013)
  • Author(s): Chand D, Yamazaki Y, Ruuth K, Schönherr C, Martinsson T, Kogner P, Attiyeh EF, Maris J, Morozova O, Marra MA, Ohira M, Nakagawara A, Sandström PE, Palmer RH, Hallberg B.
  • Journal Title: Dis Model and Mech Volume: 6 Pages: 373-382
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 4 (KLF4) suppresses neuroblastoma cell growth and determines non-tumorigenic lineage differentiation (2013)
  • Author(s): Shum CK, Lau ST, Tsoi LL, Chan LK, Yam JW, Ohir a M, Nakagawara A, Tam PK, Ngan ES.
  • Journal Title: Oncogene Volume: 32 Pages: 4086-4099
  • Peer Reviewed
• [Journal Article] RUNX3 interacts with MYCN and facilitates protein degradation in neuroblastoma. (2013)
  • Author(s): Yu F, Gao W, Yokochi T, Suenaga Y, Ando K, Ohira M, Nakamura Y, Nakagawara A.
  • Journal Title: Oncogene Volume: 33 Issue: 20 Pages: 2601-2609
  • DOI: 10.1038/onc.2013.221
  • Peer Reviewed / Open Access
• [Journal Article] Dependence receptor UNC5D mediates nerve growth factor depletion-induced neuroblastoma regression. (2013)
  • Author(s): Zhu Y, Li Y, Haraguchi S, Yu M, Ohira M, Ozaki T, Nakagawa A, Ushijima T, Isogai E, Koseki H, Nakamura Y, Kong C, Mehlen P, Arakawa H, Nakagawara A.
  • Journal Title: J Clin Invest. Volume: 123 Issue: 7 Pages: 2935-47
  • DOI: 10.1172/jci65988
  • Peer Reviewed
• [Journal Article] Stronger prognostic power of the CpG island methylator phenotype than methylation of individual genes in neuroblastomas (2013)
  • Author(s): Asada K, Watanabe N, Nakamura Y, Ohira M, Westermann F, Schwab M, Nakagawara A, Ushijima T.
  • Journal Title: Jpn J Clin Oncol Volume: 43 Issue: 6 Pages: 641-645
  • DOI: 10.1093/jjco/hyt058
  • Peer Reviewed
• [Journal Article] Novel adaptor protein Shf interacts with ALK receptor and negatively regulates its downstream signals in neuroblastoma. (2013)
  • Author(s): Takagi D
  • Journal Title: Cancer Sci Volume: 104 Issue: 5 Pages: 563-572
  • DOI: 10.1111/cas.12115
  • Peer Reviewed
• [Journal Article] A MYCN-amplified cell line derived from a long-term event-free survivor among our sixteen established neuroblastoma cell lines. (2013)
  • Author(s): Sugimoto T, Gotoh T, Yagyu S, Kuroda H, Iehara T, Hosoi H, Ohta S, Ohira M, Nakagawara A.
  • Journal Title: Cancer Lett Volume: 331 Issue: 1 Pages: 115-121
  • DOI: 10.1016/j.canlet.2012.12.011
  • Peer Reviewed
• [Journal Article] Cell culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. (2013)
  • Author(s): Chand D, Yamazaki Y, Ruuth K, Schönherr C, Martinsson T, Kogner P, Attiyeh EF, Maris J, Morozova O, Marra MA, Ohira M, Nakagawara A, Sandström PE, Palmer RH, Hallberg B.
  • Journal Title: Dis Model Mech. Volume: 6 Pages: 373-82
  • DOI: 10.1242/dmm.010348
  • Peer Reviewed
• [Journal Article] ALK fusion gene positive lung cancer and 3 cases treated with an inhibitor for ALK kinase activity (2012)
  • Author(s): Kimura H, Nakajima T, Takeuchi K, Soda M, Mano H, Iizasa T, Matsui Y, Yoshino M, Shingyoji M, Itakura M, Itami M, Ikebe D, Yokoi S, Kageyama H, Ohir a M, Nakagawara A.
  • Journal Title: Lung Cancer Volume: 75 Pages: 66-72
  • Peer Reviewed
• [Journal Article] Kruppel-like factor 4 (KLF4) suppresses neuroblastoma cell growth and determines non-tumorigenic lineage differentiation. (2012)
  • Author(s): Shum CK, Lau ST, Tsoi LL, Chan LK, Yam JW, Ohira M, Nakagawara A, Tam PK, Ngan ES.
  • Journal Title: Oncogene Volume: advance online publication Issue: 35 Pages: 4086-4099
  • DOI: 10.1038/onc.2012.437
  • Peer Reviewed
• [Journal Article] ALK fusion gene positive lung cancer and 3 cases treated with an inhibitor for ALK kinase activity. (2012)
  • Author(s): Kimura H, Nakajima T, Takeuchi K, Soda M, Mano H, Iizasa T, Matsui Y, Yoshino M, Shingyoji M, Itakura M, Itami M, Ikebe D, Yokoi S, Kageyama H, Ohira M, Nakagawara A.
  • Journal Title: Lung Cancer Volume: 75 Issue: 1 Pages: 66-72
  • DOI: 10.1016/j.lungcan.2011.05.027
  • Peer Reviewed
• [Journal Article] Expression of NLRR3 orphan receptor gene is negatively regulated by MYCN and Miz-1, and its down-regulation is associated with an unfavorable outcome in neuroblastoma (2011)
  • Author(s): Akter J, Takatori, A, Hossain S, Ozaki T, Nakazawa A, Ohir a M, Suenaga Y, Nakagawara A.
  • Journal Title: Clin Cancer Res Volume: 17 Pages: 6681-6692
  • Peer Reviewed
• [Journal Article] A novel potent tumour promoter aberrantly overexpressed in most human cancers (2011)
  • Author(s): Takahashi A, Tokita H, Takahashi K, Takeoka T, Murayama K, Tomotsune D, Ohira M, Iwamatsu A, Ohara K, Yazaki K, Koda T, Nakagawara A, Tani K
  • Journal Title: Scientific Reports Volume: 1(15) Issue: 1 Pages: 6-6
  • DOI: 10.1038/srep00015
  • Peer Reviewed
• [Journal Article] Oncogenic LMO3 collaborates with HEN2 to enhance neuroblastoma cell growth through transactivation of Mash1 (2011)
  • Author(s): Isogai E, Ohira M, Ozaki T, Oba S, Nakamura Y, Nakagawara A
  • Journal Title: PLoS ONE Volume: 6(5) Issue: 5 Pages: e19297-e19297
  • DOI: 10.1371/journal.pone.0019297
  • Peer Reviewed
• [Journal Article] Expression of NLRR3 orphan receptor gene is negatively regulated by MYCN and Miz-1, and its down-regulation is associated with unfavorable outcome in neuroblastoma (2011)
  • Author(s): Akter J, Takatori A, Hossain S, Ozaki T, Nakazawa A, Ohira M, Suenaga Y, Nakagawara A
  • Journal Title: Clin Cancer Res Volume: 17 Issue: 21 Pages: 6681-6692
  • DOI: 10.1158/1078-0432.ccr-11-0313
  • Peer Reviewed
• [Presentation] Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes (2013)
  • Author(s): 大平美紀, 他11名
  • Organizer: 米国癌学会小児癌分科会(AACR Special Conference on Pediatric Cancer At The Crossroads (AACR -PCAC))2013
  • Place of Presentation: 米国・サンディエゴ
• [Presentation] 網羅的ゲノム解析を用いたMYCN非増幅型難治性神経芽腫の予後関連ゲノム異常の検索 (2013)
  • Author(s): 大平美紀, 他8名
  • Organizer: 第55回日本小児血液・がん学会学術集会
  • Place of Presentation: 福岡
• [Presentation] 難治性中間型神経芽腫の予後に関与するゲノムプロファイルの検索 (2013)
  • Author(s): 大平美紀, 他7名
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Risk classification of neuroblastoma based on genomic profiles : For future tailor-made therapeutic strategies in Japan (2013)
  • Author(s): 大平美紀, 他10名
  • Organizer: 第45回国際小児がん学会(SIOP2013)
  • Place of Presentation: 中国・香港
• [Presentation] Prognosis-related miRNA expression profiles of neuroblastoma (2013)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第104回米国癌学会総会(AACR2013)
  • Place of Presentation: 米国・ワシントンD.C.
• [Presentation] Prognosis-related miRNA expression profiles of neuroblastoma Short title: miRNA expression in neuroblastoma (2013)
  • Author(s): M.Ohira, E.Isogai, Y.Nakamura, T.Kamijo, A.Nakagawara
  • Organizer: 第104回米国癌学会総会(AACR2013)
  • Place of Presentation: 米国・ワシントンD.C.
• [Presentation] Risk classification of neuroblastoma based on genomic profiles: For future tailor-made therapeutic strategies in Japan (2013)
  • Author(s): M.Ohira, T.Kamijo, Y.Nakamura, K.Matsumoto, M.Kumagai, A.Nakazawa, T.Takimoto, T.Fukushima, T.Tajiri, H.Ikeda, A.Nakagawara
  • Organizer: 第45回国際小児がん学会(SIOP2013)
  • Place of Presentation: 中国・香港
• [Presentation] Whole exome sequencing of 101 neuroblastomas with distinct genomic subgroups identified significantly mutated pathways in aggressive tumor subtypes (2013)
  • Author(s): M.Ohira, Y.Li, Y.Zhou, X.Li, Z.Gao, K.Tatsuno, S.Tsutsumi, S.Yamamoto, Y.Nakamura, T.Kamijo, H.Aburatani, A.Nakagawara
  • Organizer: AACR Special Conference on Pediatric Cancer At The Crossroads (AACR-PCAC)
  • Place of Presentation: 米国・サンディエゴ
• [Presentation] マイクロRNA発現レベルによる神経芽腫のリスク分類 (2012)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第54回日本小児血液・がん学会学術集会
  • Place of Presentation: 横浜
• [Presentation] Prognosis prediction of neuroblastoma subsets based on miRNA expression profiles (2012)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] 神経芽腫の予後マーカーとしてのmiRNA発現プロファイル (2012)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第19回日本遺伝子診療学会大会
  • Place of Presentation: 千葉
• [Presentation] Gene expression and genomic aberration signatures cooperatively work to improve tumor risk stratification of neuroblastoma (2012)
  • Author(s): 大平美紀, 他3名
  • Organizer: Advances in Neuroblastoma Research 2012 (ANR2012)
  • Place of Presentation: カナダ・トロント
• [Presentation] miRNA expression levels are strongly correlated with neuroblastoma prognosis (2012)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第2回日中がん研究シンポジウム
  • Place of Presentation: 千葉
• [Presentation] Gene expression and genomic aberration signatures cooperatively work to improve tumor risk stratification of neuroblastoma. (2012)
  • Author(s): Ohira M, Nakamura Y, Kamijo T, Nakagawara A.
  • Organizer: Advances in Neuroblastoma Research 2012
  • Place of Presentation: カナダ・トロント
• [Presentation] 神経芽腫の予後に相関するマイクロRNA発現パターンの検索 (2011)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第53回日本小児血液・がん学会学術集会
  • Place of Presentation: 新前橋
• [Presentation] LIM-only protein LMO3は、神経芽腫の発生母地である神経堤細胞において細胞増殖と分化を制御する (2011)
  • Author(s): 大平美紀, 他3名
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] 神経芽腫の予後に強く相関するmiRNA発現プロファイルの検索 (2011)
  • Author(s): 大平美紀, 他4名
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] Identification of prognosis-related miRNA expression profiles in neuroblastoma. (2011)
  • Author(s): Ohira M, Isogai E, Nakamura Y, Kamijo T, Nakagawara A.
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋
• [Presentation] The LIM-only protein LMO3 could regulate growth and proliferation in neural crest cells. (2011)
  • Author(s): Isogai E, Ohira M, Haraguchi S, Nakagawara A.
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋