Nakamura M, Ishida E, Shimada K, Kishi M, Nakase H, Sakaki T et al.. Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas. Lab Invest 85: 165-175

Department of Pathology, Nara Medical University School of Medicine, Nara, Japan.
Laboratory Investigation (Impact Factor: 3.68). 03/2005; 85(2):165-75. DOI: 10.1038/labinvest.3700223
Source: PubMed


Frequent allelic losses on the long arm of chromosome 22 (22q) in gliomas indicate the presence of tumor suppressor gene (TSG) at this location. However, the target gene(s) residing in this chromosome are still unknown and their putative roles in the development of astrocytic tumors, especially in secondary glioblastoma, have not yet been defined. 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 grade II diffuse astrocytomas, anaplastic astrocytomas, primary glioblastomas, and secondary glioblastomas that had evolved from lower grade astrocytomas. LOH was found at one or more loci in 33% (12/36) of grade II diffuse astrocytomas, in 40% (4/10) of anaplastic astrocytomas, in 41% (26/64) of primary glioblastomas, and in 82% (23/28) 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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    • "Obviously, the biological behaviour of meningiomas cannot be accounted by histological parameters alone [3], [4], [21], [31]. There is agreement in the literature that radical surgical extirpation is correlated with good prognosis [13], [14], [16], [22], [32], [52]. We therefore included only patients in our study whose tumor had been macroscopically completely removed, corresponding to Simpson grades I and II [43]. "
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    • "Primary and secondary glioblastoma subtypes are histopathologically indistinguishable, but differences can be demonstrated by molecular markers at the epigenetic [77], genetic [1, 18, 24], expression [65], and proteomic [108] levels (Fig. 2; Table 4). Primary glioblastomas have a greater prevalence of EGFR alterations, MDM2 duplications, PTEN mutations, and homozygous deletions of CDKN2A [1, 18]. "
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    • ". The TIMP-3 gene is located on chromosome 22q12.3, a region in which loss of heterozygosity is frequently observed in various cancers, such as pancreatic endocrine tumors and secondary glioblastoma [28] [29] [30]. Interestingly, a recent study by Bachmann et al. [15] reported that silencing of TIMP-3 gene is also associated with 5′ CpG island hypermethylation in kidney, brain, and colon cancers. "
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    ABSTRACT: Tissue inhibitor of metalloproteinase 3 (TIMP-3) promoter methylation has been linked to loss of TIMP-3 expression in various cancers. In this study, we analyzed TIMP-3 gene methylation using MethyLight assay and TIMP-3 mRNA expression using reverse transcription-polymerase chain reaction analysis in 22 esophageal cancers, 27 gastric carcinomas, and 7 cancer cell lines. We also analyzed TIMP-3 protein expression by immunohistochemistry and its association with clinicopathological characteristics in two cohorts of gastric cancer comprising a total of 347 patients. The TIMP-3 gene was more commonly methylated in adenocarcinomas of the esophagus (9/13) and stomach (9/15) than in the corresponding nonneoplastic mucosa of the esophagus (1/8; P = .024) and stomach (2/14; P = .021). In gastric cancer patients, TIMP-3 was decreased in a diffuse-type gastric cancer and in cancers with poor differentiation and was associated with poor survival (P = .04). In summary, we observed frequent TIMP-3 promoter methylation in adenocarcinomas of the esophagus and stomach and the loss of TIMP-3 expression seems to be of clinical and prognostic relevance in these cancers.
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