2004 Fiscal Year Final Research Report Summary
Detection of genetic and epigenetic pathways to glioblastomas
| Project/Area Number |
15590311
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Human pathology
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| Research Institution | Nara Medical University School of Medicine |
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Principal Investigator |
NAKAMURA Mitsutoshi Nara Medical University School of Medicine, Department of Pathology, Assistant Professor, 医学部, 講師 (00305715)
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| Co-Investigator(Kenkyū-buntansha) |
KONISHI Noboru Nara Medical University School of Medicine, Department of Pathology, Professor, 医学部, 教授 (20145832)
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| Project Period (FY) |
2003 – 2004
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| Keywords | primary glioblastoma / secondary glioblastoma / recurrent glioblastoma / TIMP-3 / epigenetic / loss of heterozygosity |
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| Research Abstract |
Frequent allelic losses on the long arm of chromosome 22 (22q) in gliomas indicate the presence of tumor suppressor gene(TSG) at this location. To compile a precise physical map for the region of common deletions in astrocytic tumors, we performed a high density loss of heterozygosity(LOH) analysis using 31 polymorphic microsatellite markers spanning 22q in a series of 36 grade II diffuse astrocytomas, 10 anaplastic astrocytomas, 64 primary glioblastomas, and 28 secondary glioblastomas that had evolved from lower grade astrocytomas. LOH was found at 1 or more loci in 33% of grade II diffuse astrocytomas, in 40% of anaplastic astrocytomas, in 41% of primary glioblastomas, and in 82% of secondary glioblastomas. Characterization of the 22q deletions in primary glioblastomas identified two sites of minimally deleted regions at 22q12.3-13.2 and 22q13.31. Interestingly, 22 of 23 secondary glioblastomas affected shared a deletion in the same small (957 kb) region of 22q12.3, a region in which the human tissue inhibitor of metalloproteinases-3(TIMP-3) is located. Investigation of the promoter methylation and expression of this gene indicated that frequent hypermethylation correlated with loss of TIMP-3 expression in secondary glioblastoma. This epigenetic change was significantly correlated to poor survival in eight patients with grade II diffuse astrocytoma. Our results suggest that a 957 kb locus, located at 22q12.3, may contain the putative TSG, TIMP-3, that appears to be relevant to progression to secondary glioblastoma and subsequently to the prognosis of grade II diffuse astrocytoma. In addition, the possibility of other putative TSGs on 22q12.3-13.2 and 22q13.31 that may also be involved in the development of primary glioblastomas cannot be ruled out.
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