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The mechanism of polyploidy and aneuploidy formation in neuroblastoma

Research Project

Project/Area Number 18390475
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatric surgery
Research InstitutionResearch Institute for Clinical Oncology, Saitama Cancer Center

Principal Investigator

KANEKO Yasuhiko  Research Institute for Clinical Oncology, Saitama Cancer Center, 臨床腫瘍研究所, 所長 (50373387)

Co-Investigator(Kenkyū-buntansha) HARUTA Masayuki  埼玉県立がんセンター, 臨床腫瘍研究所, 研究員 (80392190)
KASAI Fumio  埼玉県立がんセンター, 臨床腫瘍研究, 研究員 (60393055)
FUKUSHI Daisuke  埼玉県立がんセンター, 臨床腫瘍研究所, 研究員 (90397159)
Project Period (FY) 2006 – 2008
Project Status Completed (Fiscal Year 2008)
Budget Amount *help
¥13,620,000 (Direct Cost: ¥11,400,000、Indirect Cost: ¥2,220,000)
Fiscal Year 2008: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2007: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2006: ¥4,000,000 (Direct Cost: ¥4,000,000)
Keywords神経芽腫 / 倍数性 / 異数性染色体異常 / 3倍体腫瘍 / 2倍体腫瘍 / 中心体異常 / 3極分裂 / MYCN増幅 / 細胞質不分離 / 倍数性・異数性染色体異常 / 染色体異常 / MYCN / 異数性異常 / 倍数性異常 / M期チェックポイント遺伝子
Research Abstract

神経芽腫は乳児に発生する予後良好な3倍体(3n)腫瘍と年長児の予後不良な2倍体(2n)腫瘍に大別される。染色体数が変化する要因の1つとして、体細胞分裂時に重要な役割をもつ中心体の異常が知られている。一方、3n神経芽腫は4n細胞の3極分裂により形成されると考えられているが、3極分裂には中心体数の異常を伴うと予想される。そこで、神経芽腫の染色体異常と中心体異常の関連を解析した。乳児と年長児の神経芽腫27例をFISH解析により、染色体ploidy, 1p欠失およびMYCN増幅の有無を調べた。一方、抗γチュブリン抗体と抗βチュブリン抗体による免疫染色により、中心体の数を数え、その増幅の有無を検討した。染色体数が3倍体領域にある神経芽腫細胞株TGWにヒストンGFPを導入し、細胞分裂の様子をタイムラプス顕微鏡により経時的に観察した。
腫瘍組織27例を解析した結果、中心体増幅は3n腫瘍ではなく、2n腫瘍において検出された。2n腫瘍は予後良好群と不良群に分類され、年長児では2n細胞のみで構成されるが、乳児では多数の2n 細胞の他に少数の3n細胞と4n細胞が含まれていた(ploidy divergence)。乳児と年長児の2n腫瘍に共通して中心体が増幅していたが、ploidy divergenceが認められるのは乳児2n腫瘍だけであり、両者における中心体異常の発生機構は異なると考えられた。既に神経芽腫においてMYCN増幅は中心体増幅と相関すると報告されていたが、両者に相関はみられず、MYCN増幅は中心体増幅を誘導しないという所見を得た。一方、3n腫瘍では中心体異常は検出されなかった。4n細胞の3極分裂により3n細胞が形成されるという仮説を踏まえると、親細胞である4n細胞に中心体異常があると推測されるが、3極分裂によって形成される3n細胞の中心体数は正常であり、その後3倍体細胞は2極分裂をして増殖すると考えられた。また、乳児の2n腫瘍と3n腫瘍は共通の4n前駆細胞の細胞質不分離により発生すると推測された。
3倍体細胞の発生に必要な3極分裂が神経芽腫で生じているかどうかを検証するために、神経芽腫細胞株TGWの細胞分裂の様子を調べた。タイムラプス顕微鏡による経時的な観察により3極分裂を確認するとともに、3極分裂により3つの娘細胞が形成される所見を得た。TGW株は年長児の予後不良神経芽腫由来なので、乳児の3倍体腫瘍に想定される3極分裂と同様な機序で3極分裂が生じているかどうかについては、議論のあるところであるが、神経芽腫細胞は3極分裂を生じるポテンシャルをもつと考えられた。3n細胞は4n細胞を経て3極分裂により形成されるという仮説が支持された。

Report

(4 results)
  • 2008 Annual Research Report   Final Research Report ( PDF )
  • 2007 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (31 results)

All 2009 2008 2007 2006 Other

All Journal Article (20 results) (of which Peer Reviewed: 8 results) Presentation (10 results) Remarks (1 results)

  • [Journal Article] Centrosome amplification is correlated with ploidy divergence, but not with MYCN amplification in neuroblastoma tumors2009

    • Author(s)
      Fukushi D, Watanabe N, Kasai F, Haruta M, Kikuchi A, Kikuta A, Kato K, Nakadate H, Tsunematsu Y, Kaneko Y
    • Journal Title

      Cancer Genet Cytogenet 188

      Pages: 32-41

    • Related Report
      2008 Annual Research Report 2008 Final Research Report
  • [Journal Article] Feuerstein BG, Nakagawara A. Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature2008

    • Author(s)
      Tomioka N, Oba S, Ohira M, Misra A, Fridlyand J, Ishii S, Nakamura Y, Isogai E, Hirata T, Yoshida Y, Todo S, Kaneko Y, Albertson DG, Pinkel D
    • Journal Title

      Oncogene 27

      Pages: 441-449

    • Related Report
      2008 Final Research Report
  • [Journal Article] Novel risk stratification of patients with neuroblastoma by genomic signature, which is independent of molecular signature2008

    • Author(s)
      Tomioka N, Oba S, Ohira M, Misra A, Fridlyand J, Ishii S, Nakamura Y, Isogai E, Hirata T, Yoshida Y, Todo S, Kaneko Y, Albertson DG, Pinkel D, Feuerstein BG, Nakagawara A
    • Journal Title

      Oncogene 27

      Pages: 441-149

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel risk stratification of patients with neuroblastoma by genomic signature,which is independent of molecular signatule.2008

    • Author(s)
      Tomioka N, Oba S, Ohira M, Misra A, Fridlyand J, Ishii S, Nakamura Y, Isogai E, Hirata T, Yoshida Y, Todo S, Kaneko Y, Albertson DG, Pinkel D, Feuerstein BG, Nakaawara A.
    • Journal Title

      Oncogene 27

      Pages: 441-449

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The methylation status of RASSF1A promoter predicts responsiveness to chemotherapy and eventual cure in hepatoblastoma patients.2008

    • Author(s)
      Honda S, Haruta M, Sugawara W, Sasaki F, Ohira M, Matsunaga T, Yamaoka H, Horie H, Ohnuma N, Nakagawara A, Hjyama E, Todo S, Kaneko Y.
    • Journal Title

      Int.J.Cancer, (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Combhled BubR1 protein down-regulation and RASSF1A hypermethylation in Wilms tumors with diverse cytogenetic changes.2008

    • Author(s)
      Haruta M, Matsumoto Y, Izumi H, Watanabe N, Fukuzawa M, Matsuura S, Kaneko Y.
    • Journal Title

      Mol Carcinog, (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Duplication of paternal IGF2 or loss of maternal IGF2 imprinting occurs in half of Wilms tumors with various structural WT1Abnormalities.2008

    • Author(s)
      Haruta M, Arai Y, Sugawara W, Watanabe N, Honda S, Ohshima J, Soejima H, Nakadate H, Okita H, Hata H, Fukuzawa M, Kaneko Y
    • Journal Title

      Chromosomes Cancer (in press)

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neuroblastomas that might benefit from mass screening at 6 months of age in Japan2007

    • Author(s)
      Kaneko, Y
    • Journal Title

      Pediatr Blood & Cancer 48

      Pages: 245-246

    • Related Report
      2008 Final Research Report
  • [Journal Article] Neuroblastomas that might benefit from mass screening at 6 months of age in Japan.2007

    • Author(s)
      Kaneko.Y
    • Journal Title

      Pediatr Blood & Cancer 48

      Pages: 245-246

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma2007

    • Author(s)
      Sugawara W, Haruta M, Sasaki F, Watanabe N, Tsunematsu Y, Kikuta, A, Kaneko Y.
    • Journal Title

      Pediatr Blood & Cancer 49

      Pages: 240-249

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Duplieation of the paternal IGF2 allele in trisomy 11 and elevated expression levels of IGF2 mRNA in congenital mesoblastic nephrqma of the cellular or mixed type.2007

    • Author(s)
      Watanabe N, Haruta M, Soejima H, Fukushi D, Yokomori K, Nakadate H, Okita H, Hata JI, Fukuzawa M, Kaneko Y
    • Journal Title

      Genes Chromosomes Cancer 46

      Pages: 929-935

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neuroblastomas that might benefit from mass screening at 6 months of age in Japan2007

    • Author(s)
      Kaneko Y
    • Journal Title

      Pediatr Blood & Cancer, :,2007 48

      Pages: 245-246

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Biology of neuroblastomas that were found by mass screening at 6 months of age in Japan2006

    • Author(s)
      Kaneko Y, Kobayashi H, Watanabe N, Tomioka N, Nakagawara A
    • Journal Title

      Pediatr Blood & Cancer 46

      Pages: 285-291

    • Related Report
      2008 Final Research Report
  • [Journal Article] A.biology of neuroblastomas that were found by mass screening at 6 months of age in Japan2006

    • Author(s)
      Kaneko Y, Kobayashi H, Watanabe N, Tomioka N, Nakagawa A
    • Journal Title

      Pediatr blood & Cancer 46

      Pages: 285-291

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Association of 11q loss, trisomy 12 and prossible 16q loss with loss of imprinting of insulin-like growth factor-II in wilms tumor.2006

    • Author(s)
      Watanabe N, Nakadate H, Haruta M, Sugawara W, Sasaki F, Tsunematsu Y, Kikuta A, Fukuzawa M, Okita H, Hata J, Hidenobu H, Kaneko Y
    • Journal Title

      Genes Chromosomes Cancer 45

      Pages: 592-601

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Participation of nuclear localization signal 1 in the 3'-ETS domain of FL1 in nuclear translocation of various chimeric EWS-SLI1 oncoproteins in Ewing tumor.2006

    • Author(s)
      Honsei N, Ikuta T, Kawana K, Kaneko Y, Kawajiri K
    • Journal Title

      Int J Oncology 29

      Pages: 689-693

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Promoter hypermethylation of the RASSF1A gene predicts the poor outcome of patients with hepatoblastoma.2006

    • Author(s)
      Sugawara W, Haruta M, Sasaki F, Watanabe N, Tsunematsu Y, Kikuta A, Kaneko Y
    • Journal Title

      Pediatr Blood & Cancer (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] A cytogenetic analysis in two cases of malignant peripheral nerve sheath tumor showing hypodiploid karyotype.2006

    • Author(s)
      Ishiguro M, Iwasaki H, Takeshita M, Hirose Y, Kaneko Y
    • Journal Title

      Oncol Rep 16

      Pages: 225-232

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Establishment and characterization of a new cell line. FRTK-1, derived from human malignant rhabdoid tumor of the kidney,with overexpression of epidermal growth factor receptor and cyclooxygenase-2.2006

    • Author(s)
      Hakozaki M, Hojo H, Sato M, Kaneko Y, Watanabe N, Kikuchi S, Abe M
    • Journal Title

      Oncol Rep 16

      Pages: 265-271

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Genetic and epigenetic alterations on the short arm of chromosome 11 are involved in a majority of sporadic Wilms'tumours2006

    • Author(s)
      Sato Y, Nakadate H, Nakagawachi T, Higashimoto K, Joh K, Masaki Z, Uozumi J, Kaneko Y, Mukai T, Sejima H
    • Journal Title

      Br J Cancer 95

      Pages: 541-547

    • Related Report
      2006 Annual Research Report
  • [Presentation] Centrosome amplification is correlated with ploidy instability in infant neuroblastoma (NB) tumors, but not with MYCN amplification in infant and childhood NB tumors or cell line2008

    • Author(s)
      Kaneko Y, Fukushi D, Watanabe N, Kasai F, Haruta M, Kikuchi A, Kikuta A, Tsunematsu Y
    • Organizer
      Advances in Neuroblastoma Research
    • Place of Presentation
      千葉
    • Related Report
      2008 Final Research Report
  • [Presentation] 乳児と小児2倍体神経芽腫の特徴-中心体の増幅と異数性細胞の混在-2008

    • Author(s)
      笠井文生、福士大輔、渡辺直樹、春田雅之、金子安比古
    • Organizer
      第67回日本癌学会
    • Place of Presentation
      名古屋
    • Related Report
      2008 Annual Research Report 2008 Final Research Report
  • [Presentation] Centrosome amplification is correlated with ploidy instability in infant neuroblastoma (NB) tumors, but not with MYCN amplification in infant and childhood NB tumors or cell line2008

    • Author(s)
      Kaneko Y
    • Organizer
      Advances in Neuroblastoma Reserch
    • Place of Presentation
      千葉
    • Related Report
      2008 Annual Research Report
  • [Presentation] 神経芽腫のploidy異常の発生に3極分極が関与するのか?2007

    • Author(s)
      福士大輔、渡辺直樹、春田雅之、金子安比古
    • Organizer
      第66回日本癌学会
    • Place of Presentation
      横浜
    • Related Report
      2008 Final Research Report 2007 Annual Research Report
  • [Presentation] Spontaneous regression of neuroblastoma and the mass screening program at 6 months of age2007

    • Author(s)
      金子安比古
    • Organizer
      第1回依存性受容体研究会および第10回神経芽腫研究会合同会議
    • Place of Presentation
      東京
    • Related Report
      2008 Final Research Report
  • [Presentation] WT1およびIGF2遺伝子のSNP arrayとH19-DMR分析により証明されたWT1変異型Wilms腫瘍の不均一性.2007

    • Author(s)
      金子 安比古
    • Organizer
      第66回日本癌学会
    • Place of Presentation
      横浜
    • Related Report
      2007 Annual Research Report
  • [Presentation] Spontaneous regression of neuroblastoma and the mass screening program at 6 months of age.2007

    • Author(s)
      金子 安比古
    • Organizer
      第1回依存性受容体研究会および第10回神経芽腫研究会合同会議.
    • Place of Presentation
      東京.
    • Related Report
      2007 Annual Research Report
  • [Presentation] WT1およびIGF2遺伝子のSNP arrayとH19-DMR分析により証明されたWT1変異型Wilms腫瘍の不均一性.2007

    • Author(s)
      金子 安比古
    • Organizer
      第52回人類遺伝学会.
    • Place of Presentation
      東京.
    • Related Report
      2007 Annual Research Report
  • [Presentation] 神経芽腫のploidy異常の発生に中心体異常は関与するのか?2006

    • Author(s)
      福士大輔、渡辺直樹、春田雅之、金子安比古
    • Organizer
      第22回日本小児がん学会
    • Place of Presentation
      大阪
    • Related Report
      2008 Final Research Report
  • [Presentation] マススクリ-ニングで発見された神経芽腫におけるアポトーシス関連遺伝子のメチル化異常2006

    • Author(s)
      春田雅之、大平美紀、中川原章、金子安比古
    • Organizer
      第22回日本小児がん学会.
    • Place of Presentation
      大阪
    • Related Report
      2008 Final Research Report
  • [Remarks]

    • URL

      http://www.saitama-cc.jp/rinsyousyuyou_labo/index.html

    • Related Report
      2008 Final Research Report

URL: 

Published: 2006-04-01   Modified: 2016-04-21  

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