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The development of rapid diagnostic system for detecting a predisposition to cancer in early childhood

Research Project

Project/Area Number 07557232
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Pediatrics
Research InstitutionUniversity of Tokyo

Principal Investigator

HAYASHI Yasuhide  Univ.of Tokyo, Faculty of Medicine, Associate Professor, 医学部・附属病院, 講師 (30238133)

Co-Investigator(Kenkyū-buntansha) YAMAMORI Shunji  Mitsubishi Biochemical Cooperation, Molecular Department, Director, 遺伝子解析部, 部長
KOBAYASHI Miyuki  Univ.of Tokyo, Faculty of Medicine, Assistant Professor, 医学部・附属病院, 助手 (60205391)
YANAGISAWA Masayoshi  Univ.of Tokyo, Faculty of Medicine, Professor, 医学部・附属病院, 助手 (90049031)
小林 茂俊  東京大学, 医学部・附属病院, 助手 (70260487)
森脇 浩一  東京大学, 医学部・附属病院, 助手 (10251274)
Project Period (FY) 1995 – 1997
Project Status Completed (Fiscal Year 1997)
Budget Amount *help
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 1997: ¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1996: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsacute lymphoblastic leukemia / neuroblastoma / tumor suppressor gene / p53 gene / RAS gene / p16 gene / p73 gene / p19 gene / 白血病 / 小児がん / 癌抑制遺伝子 / P15遺伝子 / DCC遺伝子 / NF1遺伝子 / 固形腫瘍 / PCR-SSCP / 悪性腫瘍 / 癌遺伝子 / p16遺伝子 / RB遺伝子
Research Abstract

Homozygous deletions (HD) of p16 and p15 genes and mutations of pl6, RAS and p53 genes were examined in acute lymphoblastic leukemia (ALL) and childhood solid tumors. Rearrangements of p16 were higher in cell lines and fresh leukemia without t(1 ; 19) than those with t(l ; 19). Remarkably, mutations were found in 3 of the primary cases (5%). As for leukemia with MLL rearrangement (MLL+), HD of the p16 and p15 genes was found in 5 (11%) of 19 acute myeloid leukemias (AMLs). PCR-single strand conformation polymorphism (SSCP) showed no mutation in the 32 patients tested. Our results suggest that alterations of 16 and p15 genes are involved in a subset of acute leukemias with MLL.Mutations of the p53 gene were found in 3 of 57 (5%) T-ALL patients at diagnosis, 1 of 14 (7%) patients at relapse and in 12 of 18 (67%) cell lines, All patients with p53 mutations in the course of disease died. Mutations of the p21 gene were not identified in 71 fresh samples and in 18 cell lines. N-RAS mutations … More were found in 2 of 57 (4%) fresh T-ALL patients only at diagnosis, and 4 of 118 cell lines (22%). Alterations of the p16 gene were found in 18 of 47(38%) patients at diagnosis and in 7 of 14(50%) at relapse (not significant). There were no differences in the frequency of alteration of the p16 and p15 genes between event-free patients and the remaining patients. Furthermore, we found the methylation of p16 gene in 3 of 7 patients lacking homozygous deletions, suggesting higher frequency of p16 inactivation than previous reports in T-ALL.
N-myc, p16, DCC, DPC4, MADR2 and p73 genes were analyzed in neuroblastoma (NB). HD of p16 genre was not found in 81 samples. PCR-SSCP analysis identified only missense mutation, suggesting polymorphism. Absence or decreased expression of pl6 gene was found in 6 of 10 cell lines. Hypermethylation of the p16 gene was found in 12 of 19 cell lines, suggesting that hypermethylation plays an important role for the development or progression of neuroblastoma. Absence or reduced expression of DCC gene was found in half of the samples. PCR-SSCP analysis of DCC gene showed only missense mutation, suggesting polymorphism. Alterations of DPC4 and MDRR2 genes were relatively rare. These results suggest that DCC gene plays an important role in the dissemination of NB, and that DPC4 and MAD2 gene are not involved in the development of NB.This study may counribute to the development of rapid diagnostic system for detecting a predisposition to cancer in early childhood. Less

Report

(4 results)
  • 1997 Annual Research Report   Final Research Report Summary
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • Research Products

    (41 results)

All Other

All Publications (41 results)

  • [Publications] Ohnishi H.et al.: "Homozygous deletions of p16/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia." Blood. 86. 1269-1275 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamura M.et al.: "Mutations of the p53 and ras genes in childhood t(1;19)-acute lymphoblastic leukemia." Blood. 85. 2546-2552 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H.et al.: "Homozygous deletions of p16/MTS1 and p15/MTS2 in t)1;19)-negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood." Leukemia. 10. 1104-1110 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H.et al: "Alteration of p16 and p15 genes in acute leukemia with MLL gene rearrangements and thier corelation with clinical features." Leukemia. 11. 2120-2124 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takita J.et al.: "Deletion map of Chromosome 9 and p16(CDKN2A) gene alterations in neuroblastoma." Cancer Res.57. 907-912 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kong X-T.et al.: "Expression and mutational analysis of the DCC,DPC4,and MADR2/JV18-1 genes in neuroblastoma." Cancer Res.57. 3772-3778 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H,Kawamura M.Ida K,Sheng X.M,Hanada R,Nobori T,Yamamori S,Hayashi Y: "Homozygous deletions of pl6/MTS1 gene are frequent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia" Blood. 86. 1269-1275 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kawamura M,Kikuchi A,Kobayashi S,Hanada R,Yamamoto K,Horibe H,Shikano T,Ueda K,Hayashi K,Sekiya T,Hayashi Y: "Mutations of the p53 and ras genes in childhood t (1 ; 19) -acute lymphoblastic leukemia" Blood. 85. 2546-2552 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H,Kawamura M,Hanada R,Bessho F,Hayashi Y,et al.: "Homozygous deletions of p16/MTS1 and pl5/MTS2 in t) 1 ; 19) -negative but not in t (1 ; 19) -positive B precursor acute lymphoblastic leukemia in childhood" Leukemia. 10. 1104-1110 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Ohnishi H,Guo SX,Ida K,Taki T,Naritaka S,Bessho F,Yanagisawa M,Hanada R,Eguchi M,Kamada N,Kita K,Yamamori S,Hayashi Y.: "Alteration of pl6 and pl5 genes in acute leukemia with MLL gene rearrangements and thier corelation with clinical features." Leukemia. 11. 2120-2124 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takita J,Hayashi Y,Kohno T,Yamaguchi N,Hanada R,Yamamoto K,Yokota J.: "Deletion map of Chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma." Cancer Res. 57. 907-912 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Kong X-T,Choi Sh, Xu Feng, Chen T,Hayashi Y: "Expression and mutational analysis of the DCC,DPC4, and MADR2/JV18-1 genes in neuroblastoma" Cancer Res. 57. 3772-3778 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1997 Final Research Report Summary
  • [Publications] Takita J, et al.: "Deletion map of chromosome 9 and p16 (CDKN2A) gene alterations in neuroblastoma." Cancer Research. 57. 907-912 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kong X-T, et al.: "Consistent detection of TLS/FUS-ERG chimeric transcripts in acute myeloid leukemia with t (16;21) (p11;q22) and identification of a novel transcript." Blood. 89. 1192-1199 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Yamamoto K, et al.: "Natural history of neuroblastoma found by mass screening." Lancet. 349. 1102 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Kong X-T, et al.: "Expression and mutational analysis of the DCC,DPC4,and MADR2/JV18-1 genes in neuroblastoma." Cancer Research. 57. 3772-3778 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Taki T, et al.: "The t (11;16) (q23;p13) translocation in myelodysplastic syndrome fuses the MLL gene to the CBP gene." Blood. 89. 3945-3950 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ida K, et al.: "Adenoviral E1A-associated protein p300 is involved in acute myeloid leukemia with t (11;22) (q23;q13)" Blood. 12. 4699-4704 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Tomohiko Taki: "Fusion of the MLL gene with two differeut geues,AF6 and AF-5α,by a complex translocation involving chromosomes 5,6,8 and 11 in intant leukemia" Oncogene. 13. 2121-2130 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shigetoshi Kobayashi: "Mutations of the Btk gene in twelve unrelated families with X-linked agdmmaglobulinemia in Japan:Immunological phenctypes aie inconsistent with the location of the mutations" Human Genetics. 97. 424-430 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroaki Ohnishi: "Infrequent mutations of the p53 gene in hepatoblastomas" Gene Chromosomes Cancer. 15. 187-190 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Hiroaki Ohnishi: "Homozygous deletions of p16/MTS1 and P15/MTS2 genes in t(1;19)-negative but not in t(1;19)-positive B precursor acute lymphoblastic leukemia in childhood" Leukemia. 10. 1104-1110 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tomohiko Taki: "Frequency and clinical significance of the MLL gene rearrangemongts in infant acute lenkemia." Leukemia. 10. 1303-1307 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kakuda: "A novel human leukaemic cell line,CTS,has a t(6;11)chromosomal translocation and characteristics of pluripotent stem cells." British Journal of Haematology. 95. 306-318 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshiaki Tsuchida: "Genetic clinical markers of human neuroblastomd with special reference to N-myc oncogene:Amplified or not amplitied?-Overview" Tumor Biology. 17. 65-74 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Akira Inoue: "Competitive polymerase chain reaction for the quantification of N-myc gene number in neuroblastomd" Tumor Biology. 17. 262-270 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Atushi Ohshima: "11q23 aberation is an additional chromosomal change in de movo acute leukemia after treatment with Etoposido and mitoxantrono." American Journal of Hematology. 53. 264-266 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Junko Takita: "Deletion map of chromosome 9 and p16(CDKN2A)gene alterations in neuroblastoma." Cancer Research. 1997年4月(発表予定). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Kohmei Ida: "Detection of chimeric mRNA by reverse transcriptase chain reaction for diagnosis and monitoring of acuto/eukemias with 11q23 abnormalities" Medical Pediatric Oncology. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Hirofumi Kobayashi: "Inversion of chromosome 11,inV(11)(p15q22)as a recurring chromosomal aberration associated with denovo and secondary myeloid malignancies." Gene Chromosomes Cancer. (in press).

    • Related Report
      1996 Annual Research Report
  • [Publications] Kawamura M.: "Mutations of the p53 and ras genes in childhood t(1:19)-acute lymphoblastic leukemia." Blood. 85. 2546-2552 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ohnishi H.: "Homozygous deletion of p16/MTS1 gene are freguent but mutations are infrequent in childhood T-cell acute lymphoblastic leukemia." Blood. 86. 1269-1275 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Yamamoto K.: "Mass screening and age specific incidence of neuroblastoma in Saitama Prefecture, Japan." Journal of clinical Oncology. 13. 2033-2038 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Roulston D.: "Therapy-ralated acute leukemia associated with t(11,23)after primary acute myeloid leukemia with(8;21):A report of two cases." Blood. 86. 3613-3614 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ida K.: "EWS-FLI1 and EWS-ERG Chimeric. mRNAs in Ewing's sarcoma and primitive neuroectodermal tumor." International Journal of Cancer. 63. 500-504 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takita J.: "Allelotype of neuroblastoma." Oncogene. 11. 1829-1834 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ito E.: "Expression of erythroid-specific genes in acute megakaryoblastic leukemia and transient myeloproliferative disorder in Down's syndrome." British Journal of Haematlogy. 90. 607-614 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Minegishi M.: "A human CD4^-CD8^- T-cell receptor αβ^+T leukemic cell line undergoing phytohemaggulutinin-induced apoptosis." Leukemia Research. 19. 433-442 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Honma Y.: "Treatment of philadelphia-ehromosome-positive human leukemia in SCID mouse model with herbimycin A, bcr-abl tyrosin kinase activity inhibitor." International Journal of Cancer. 60. 685-688 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Ohnishi H.: "Infrequent mutations of the p53 gene in hepatoblastomas." Genes Chromosomes Cancer. (in press).

    • Related Report
      1995 Annual Research Report
  • [Publications] 林 泰秀: "遺伝子診断実践ガイド-Pre B-ALLとT(1;19)-" 中外医学社, 485 (1995)

    • Related Report
      1995 Annual Research Report

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Published: 1996-04-01   Modified: 2016-04-21  

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