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Molecular and clinicopathological analysis of tumor suppressor genes in neuroblastoma using the BAC contig spanning chromosome 1p36

Research Project

Project/Area Number 13470156
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionThe University of Tokyo

Principal Investigator

TAKITA Junko (2003)  The University of Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (00359621)

川口 裕之 (2001-2002)  東京大学, 医学部附属病院, 助手 (00313130)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Miyuki  The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (60205391)
IDA Kohmei  The University or Tokyo, Faculty of Medicine, Assistant, 医学部附属病院, 助手 (60313128)
HAYASHI Yasuhide  The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (30238133)
滝田 順子  東京大学, 医学部附属病院, 助手
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥4,900,000 (Direct Cost: ¥4,900,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordsneuroblastoma / 1pLOH / KIF1B-β gene / DFF45 / Tumor suppressor gene / KIF1B-α gene / BAC contig / Charcot-Marie Tooth disease type 2 / KIFIB gene / PEX 14 / BACコンティング / KIF1B gene
Research Abstract

To identify candidate tumor suppressor genes on chromosome 1p36 for neuroblastoma (NB), we screened homozygous deletions on 1p35-36 in NB cell lines by PCR according to a high-density sequence tagged site (STS)-content map spanning, approximately 35 Mb on 1p35-36. Among 25 NB cell lines, one cell line, NB-1, showed 〜 480 kb homozygously deleted region at 1p36.2. We identified 7 known genes, including the DFF45, KIF1B-β and KIF1B-α genes in this deleted region. To assess whether the inactivation of DFF45, KIF1B-β and/or KIF1B-α plays a role in the pathogenesis of NB, we examined the involvement of both these genes in NB. Six novel variant transcripts of the DFF45 gene were found in NB cell lines, but not in normal adrenal grand and peripheral blood. The discrepancy between normal transcript and those variants may affect apoptosis pathway. However, no mutations of the DFF45 gene were detected by PCR-SSCP We determined the genomic structure of the human KIF1B-β and KIF1B-α genes and found … More that these genes have at least 47 exons and 23 exons, respectively. Allelic imbalance (AI) analysis of the KIF1B-β gene revealed relatively high incidence of AI (38%) in NBs. Obvious expression in all NB cell lines was detected except NB-1. Two missense mutation, 5 silent mutations and several polymorphisms of the KIF1B-β and KIF1B-α genes were observed. Although the missense mutation was located in the cargo domain, it is not known whether this mutation is functionally significant or not. Thus, these findings suggest that the DFF45, KIF1B-β and KIF1B-α genes may not be candidate tumor suppressor genes for NB.
Charcot-Marie-Tooth disease type 2A (CMT2A) was previously mapped to an interval containing KIF1B. We show that CMT2A patients contain a loss-of-function mutation in the motor domain of the KIF1B-β gene. This is clear indication that defects in axonal transport due to a mutated motor protein can underlie human peripheral neuropathies the most common inherited peripheral neuropathy.
To investigate the various genetic characteristics between the early-and advanced-stages of NB and identify the candidate genes involved in NB progression, we performed DNA microarray analysis in a total of 20 primary tumors. A two-way clustering analysis based on the expression pattern of approximately 500 of 1700 genes revealed genetic subgroups in these samples. Although 9 of 13 early-stage tumors (69%) and 4 of 6 advanced-stage tumors (67%) were classified as the same cluster, respectively, the remaining tumors showed different expression profiles. This indicates that both the early-and advanced-stage tumors were heterogeneous. Based on the microarray data, we identified the API2, p19INK4D, and BAF60c genes that are predominantly expressed in either the early-or advanced-stage of NB. For better assess the prognostic value of these gene expressions in NB, real-time PCR was carried out in 50 primary tumors. The expression of both the API2 and p19INK4D genes was significantly higher in the early-stage group than the advanced-stage group (P=0.002 and 0.003, respectively), whereas the expression of the BAF60c gene was significantly reduced in the early stage group (P=0.02). Therefore, it is possible that the API2, p19INK4D, and BAF60c genes are candidates as novel prognostic markers for NB. Less

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (44 results)

All Other

All Publications (44 results)

  • [Publications] Takita J: "Gene Expression Profiling and Identification of Novel Prognostic Maker Gene in Neuroblastoma."Genes Chromosomes Cancer. (in press). (2004)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Obana K: "Aberrations of p16INK4A, p14ARF and p15INK4B genes in pediatric solid tumors."Int J Oncol.. 23・4. 1151-1157 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen YY: "Genomic structure and mutational analysis of the human KIF1Balpha gene located at 1p36.2 in neuroblastoma."Int J Oncol.. 23・3. 737-744 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Taketani T: "AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies."Genes Chromosomes Cancer.. 38・1. 1-7 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagura M: "The kinesin superfamily protein Rab6KIFL is not involved in the pathophysiology of Charcot-Marie-Tooth disease type 4C."Int J Mol Med.. 11・1. 45-47 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Xu G: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome."Blood. 102・8. 2960-2968 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Taketani T: "Mutation of the AML1/RUNX1 gene in a transient myeloproliferative disorder patient with Down syndrome."Leukemia. 16・9. 1866-1867 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yang HW: "Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2."Oncogene. 20・36. 5075-5083 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takita J: "Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma"Oncogene. 20・32. 4424-4432 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen YZ: "Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36."Genes Chromosomes Cancer. 31・4. 326-332 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yang HW: "DNA fragmentation factor 45 (DFF45) gene at 1p36.2 is homozygously deleted and encodes variant transcripts in neuroblastoma cell line."Neoplasia. 3・2. 165-169 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhao C: "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta."Cell. 105・5. 587-597 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Liu M: "Loss of p73 gene expression in lymphoid leukemia cell lines is associated with hypermethylation."Leuk Res.. 25・6. 441-447 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takita J.: "Gene Expression Profiling and Identification of Novel Prognostic Maker Gene in Neuroblastoma."Genes Chromosomes Cancer. (in press). (2004)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Obana K: "Aberrations of p16INK4A, p14ARF and p15INK4B genes in pediatric solid tumors."Int J Oncol. 23. 1151-1157 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen YY: "Genomic structure and mutational analysis of the human KIF1Balpha gene located at 1p36.2 in neuroblastoma."Int J Oncol. 23. 737-744 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Taketani T: "AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies."Genes Chromosomes Cancer. 38. 1-7 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Nagura M: "The kinesin superfamily protein Rab6KIFL is not involved in the pathophysiology of Charcot-Marie-Tooth disease type 4C."Int J Mol Med. 11. 45-47 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Xu G.: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome."Blood.. 102.8. 2960-2968 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Taketani T: "Mutation of the AML1/RUNX1 gene in a transient myeloproliferative disorder patient with Down syndrome."Leukemia. 16. 1866-1867 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yang HW: "Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2."Oncogene. 20. 5075-5083 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takita J: "Allelic imbalance on chromosome 2q and alterations of the caspase 8 gene in neuroblastoma"Oncogene. 20. 4424-4432 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Chen YZ: "Homozygous deletion in a neuroblastoma cell line defined by a high-density STS map spanning human chromosome band 1p36."Genes Chromosomes Cancer. 31. 326-332 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Yang HW: "DNA fragmentation factor 45 (DFF45) gene at 1p36.2 is homozygously deleted and encodes variant transcripts in neuroblastoma cell line."Neoplasia. 3. 165-169 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Zhao C: "Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bbeta."Cell. 105. 587-597 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Liu M: "Loss of p73 gene expression in lymphoid leukemia cell lines is associated with hypermethylation"Leuk Res. 25. 441-447 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Takita J: "Gene Expression Profiling and Identification of Novel Prognostic Marker Gene in Neuroblastoma."Genes Chromosomes Cancer. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Obana K: "Aberrations of p16INK4A, p14ARF and p15INK4B genes in pediatric solid tumors."Int J Oncol.. 23・4. 1151-1157 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Chen YY: "Genomic structure and mutational analysis of the human KIF1Balpha gene located at 1p36.2 in neuroblastoma."Int J Oncol.. 23・3. 737-744 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Taketani T: "AML1/RUNX1 mutations are infrequent, but related to AML-M0, acquired trisomy 21, and leukemic transformation in pediatric hematologic malignancies."Genes Chromosomes Cancer. 38・1. 1-7 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Nagura M: "The kinesin superfamily protein Rab6KIFL is not involved in the pathophysiology of Charcot-Marie-Tooth disease type 4C."Int J Mol Med.. 11・1. 45-47 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Xu G: "Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome."Blood. 102・8. 2960-2968 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Taketani T: "The HOXD11 gene is fused to the NUP98 gene in acute myeloid leukemia with the t(2;11)(q31;p15)"Cancer Res. 62. 33-37 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ono R: "SEPTIN6, a Human Homologue to Mouse Septin6, Is Fused to MLL in Infant Acute Myeloid Leukemia with Complex Chromosomal Abnormalities Involving 11q23 and Xq24"Cancer Res. 62. 333-337 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Uno K: "Aberrations of the hSNF5/INI1 gene are restricted to malignant rhabdoid tumors or atypical teratoid/rhabdoid tumors in pediatric solid tumors"Genes Chromosomes Cancer. 34. 33-41 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taketani T: "The t(7;11)(p15;p15) in acute myeloid leukemia results in fusion of the NUP98 gene with a HOXA cluster gene, HOXA13, but not HOXA9"Genes Chromosomes Cancer. 34. 437-443 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ono R: "LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23)"Cancer Res. 62. 4075-4080 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Taketani T: "Novel NUP98-HOXC11 Fusion Gene Resulted from a Chromosomal Break within Exon 1 of HOXC11 in Acute Myeloid Leukemia with t(11;12)(p15;q13)"Cancer Res. 62. 4571-4574 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Liu M.: "Loss of p73 gene expression in lymphoid leukemia cell lines is associated with hypermethylation"Leuk Res. 25. 441-447 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yang HW.: "Genomic structure and mutational analysis of the human KIF1B gene which is homozygously deleted in neuroblastoma at chromosome 1p36.2"Oncogene. 16. 5075-5083 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Chen YZ.: "Homozygous deletion in a neuroblastoma cell line defined by a high density STS map spanning human chromosome band 1p36"Genes Chromosomes Cancer. 31. 326-332 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Yang HW.: "DNA fragmentation factor 45 (DFF45) gene at 1p36.2 Is homozygously deleted and encodes variant transcripts in neuroblastoma cell line"Neoplasia. 3. 165-169 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Zhao C.: "Charcot-marie tooth disease type 2a caused by mutation in a microtubule motor kiflbbeta"Cell. 105. 587-597 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Ono R.: "SEPTIN6, a Human Homologue to Mouse Septin6, Is Fused to MLL in Infant Acute Myeloid Leukemia with Complex Chromosomal Abnormalities Involving 11q23 and Xp24"Cancer Res. 62. 333-337 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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