Frequent LOH on 22q12.3 and TIMP-3 inactivation occur in the progression to secondary glioblastomas

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. 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.

TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells

“…Silencing of TIMP3 through promoter hypermethylation has been associated with poor prognosis in a range of human cancers including kidney, brain, colon (Bachman et al, 1999), non-small cell lung (Zochbauer-Muller et al, 2001) and meningiomas (Barski et al, 2010). Loss of TIMP3 expression, through loss of heterozigosity on chromosome 22q, is frequently observed in various cancers, such as secondary glioblastoma (Nakamura et al, 2005) and clear renal cell carcinomas (Masson et al, 2010). Evidence is emerging that downregulation of TIMP3 expression in tumors can be achieved also through deregulation of microRNAs, as TIMP3 is a target of several microRNAs upregulated in human tumors such as miR21, miR181b, miR221 and 222 (Gabriely et al, 2008;Garofalo et al, 2009;Wang et al, 2010).…”

The Role of Matrix Metalloproteinases a nd Tissue Inhibitors of Metalloproteinases in the Progression of Astrocytomas

“…Gonzalez- Gomez et al (2003aGomez et al ( , 2003b have shown that the promoter region of this gene is hypermethylated in glioblastomas, especially in secondary glioblastomas, and in medulloblastomas. Nakamura et al (2005) have also found that the loss of heterozygosity in region 22q12.3, the region containing the TIMP-gene, is a frequent event in glioblastomas. These authors also suggested that these molecular alterations may be the primary cause of decreased expression of TIMP-3 in high-grade astrocytic tumors.…”

“…These authors also suggested that these molecular alterations may be the primary cause of decreased expression of TIMP-3 in high-grade astrocytic tumors. Nakamura et al (2005) have shown that hypermethylation of TIMP-3, and the consequent reduced expression of the gene, is an important factor in the poor survival of patients affected by highly malignant tumors.…”

Genetic Profiling: Searching for Novel Genetic Aberrations in Glioblastoma

“…Frequent allelic losses on 22q indicating the presence of tumor suppressor genes have been found in primary and secondary glioblastomas [69]. LOH of 22q identified two sites of minimally deleted regions at 22q12.3-13.2 and 22q13.31 in primary glioblastomas and in most of the secondary glioblastomas.…”

“…As its name implies, expression of TIMP-3 inhibits metalloprotease activity and impair glioblastoma migration and invasiveness [70]. Expectedly, deletion of TIMP-3 enhances glioblastoma invasiveness [69].…”