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Molecular genetic investigation of Japanese cutaneous melanoma

Research Project

Project/Area Number 09670868
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Dermatology
Research InstitutionKANAZAWA UNIVERSITY

Principal Investigator

TAKATA Minoru  Kanazawa University, School of medicine, Associate Professor, 医学部, 助教授 (20154784)

Co-Investigator(Kenkyū-buntansha) TAKEHARA Kazuhiko  Kanazawa University, School of medicine, Professor, 医学部, 教授 (50142253)
HATTA Naohito  Kanazawa University, School of medicine, Assistant, 医学部, 助手 (30272959)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1998: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1997: ¥1,000,000 (Direct Cost: ¥1,000,000)
Keywordsmelanoma / p16 / tumor suppressor gene / metastasis / loss of heterozygosity / chromosome / microsatellites / 転移抑制遺伝子 / 第9染色体 / p16
Research Abstract

In a systematical analysis in 46 Japnese sporadic primary cutaneous melanomas, we detected loss of heterozygosity (LOH) of chromosome region 9p21 (where the p16 resides) in 11 (24%) tumors. Direct sequencing, however, revealed no somatic mutation of the p16 gene. Further sequencing analyses in 19 additional tumours with no evidence of LOH of 9p21 identified only one heterozygous C->T mutation at codon 81. De novo methylation of the promoter 5'CpG island of the p16 gene, which would lead to transcriptional silencing, was not demonstrated in any of these 12 tumours harboring 9p21 LOH or heterozygous p16 mutation by methylation-specific PCR assay. Nonetheless, complete loss of p16 protein, most likely due to homozygous deletion of the p16 gene, was observed in 6 (15%) out of 39 evaluable cases by immunohistochemical analyses on frozen sections. The results show that inactivation of p16 is not as frequent in primary melanoma as has been reported in cell lines, and warrant further search for another tumour suppressor on 9p21 which is likely to be more important in the initiation of melanoma. Simultaneous investigation examining corresponding metastases in 14 cases showed complete loss of p16 expression during matastatic progression in 4 cases, suggesting that inactivation of p16 plays an important role in progression (rather than initiation) of sporadic melanoma. This analysis also compared LOH of chromosome arms 6q, 9p, 9q, 10q, 11q and 18q, and provided clear evidence that in 3 cases clones of cells found in the sites of metastasis did not derive from the dominant subclone within the primary tumor, indicating that a linear model of melanoma progression is too simplistic, as there is likely to be considerable genetic heterogeneity at the earliest stages of tumourigenesis and that metastases from the same tumor may harbor different genetic change.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (18 results)

All Other

All Publications (18 results)

  • [Publications] Morita R, Fujimoto A, Hatta N, Takehara K, and Takata M: "Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression"J Invest Dermatol. 111. 919-924 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujimoto A, Morita R, Hatta N, Takehara K, Takata M: "p16^<INK4a> inactivation is not frequent in uncultured sporadic primary cutaneous melanoma"Oncogene. 18. 2527-2532 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takata M, Morita R, Takehara K: "Clonal heterogeneity in sporadic melanomas as revealed by loss-of-heterozygosity analysis"Int J Cancer. 85. 492-497 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Morita R, Fujimoto A, Hatta N, Takehara K, and Takata M: "Comparison of genetic profiles between primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression."J Invest Dermatol. 111(6). 919-924 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Fujimoto A, Morita R, Hatta N, Takehara K, Takata M: "p16ィイD1INK4aィエD1 inactivation is not frequent in uncultured sporadic primary cutaneous melanoma."Oncogene. 18. 2527-2532 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takata M, Morita R, Takehara K: "Clonal heterogeneity in sporadic melanomas as revealed by loss-of-heterozygosity analysis."Int J Cancer. 85. 492-497 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Morita R,Fujimoto A,Hatta N,Takehara K,Takata M.: "Comparison of genetic profiles in primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression"J Invest Dermatol. 111・(6). 919-924 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] Fujimoto A,Morita R,Hatta N,Takehara K,Takata M.: "P16INK4a inactivation is not frequent in sporadic primary melanoma"Oncogene. 18. 2527-2532 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Takata M,Morita R,Takehara K: "Clonal heterogeneity in sporadic melanoma as revealed by loss of heterozygosity analysis"Int J Cancer. 85. 492-497 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] 高田実: "皮膚癌の遺伝子異常(3)悪性黒色腫の遺伝子異常"皮膚科の臨床. 39. 689-694 (1997)

    • Related Report
      1999 Annual Research Report
  • [Publications] 高田実: "皮膚癌の遺伝子異常;最近の話題"皮膚病診療. 20. 950-953 (1998)

    • Related Report
      1999 Annual Research Report
  • [Publications] 高田実: "皮膚癌と癌遺伝子癌抑制遺伝子"Pharma Medica. 17. 43-47 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] 高田 実: "メラノサイトの癌化と遺伝子異常.悪性黒色腫の診断・治療指針"金原出版 (印刷中).

    • Related Report
      1999 Annual Research Report
  • [Publications] Morita R,Fujimoto A,Hatta N,Takehara K,Takata M.: "Comparison of genetic profiles in primary melanomas and their metastases reveals genetic alterations and clonal evolution during progression" J Invest Dermatol. 111(6). 919-924 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Fujimoto A,Morita R,Hatta N,Takehara K,Takata: "P16INK4a inactivation is not so frequent in sporadic primary melanoma" Oncogene. 印刷中.

    • Related Report
      1998 Annual Research Report
  • [Publications] 高田 実: "皮膚癌の遺伝子異常(3)悪性黒色腫の遺伝子異常" 皮膚科の臨床. 39(5). 689-694 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] 高田 実: "皮膚癌の遺伝子異常;最近の話題" 皮膚病診療. 20(11). 950-953 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 高田 実: "皮膚癌の遺伝子異常(3)悪性黒色腫の遺伝子異常" 皮膚科の臨床. 39. 689-694 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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