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Abstract
BackgroundMalignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Besides sharing common growth features with other types of solid tumors, gliomas are highly invasive into adjacent brain tissue, which renders them particularly aggressive and their surgical resection inefficient. Therefore, insights into glioma formation are of fundamental interest in order to provide novel molecular targets for diagnostic purposes and potential anti-cancer drugs. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. TRIM3 is located within the loss of allelic heterozygosity (LOH) hotspot of chromosome segment 11p15.5, indicating a potential role in tumor suppression. ...MethodsHere we analyze 70 primary human gliomas of all types and grades and report somatic deletion mapping as well as single nucleotide polymorphism analysis together with quantitative real-time PCR of chromosome segment 11p15.5.ResultsOur analysis identifies LOH in 17 cases (24%) of primary human glioma which defines a common 130 kb-wide interval within the TRIM3 locus as a minimal area of loss. We further detect altered genomic dosage of TRIM3 in two glioma cases with LOH at 11p15.5, indicating homozygous deletions of TRIM3.ConclusionLoss of heterozygosity of chromosome segment 11p15.5 in malignant gliomas suggests TRIM3 as a candidate brain tumor suppressor gene.
Highlights
Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies
Several genes are contained within this interval that might be involved in brain development and/or tumor suppression, including Tripartite motif protein 3 (TRIM3) and a cluster of genes encoding the more distantly related TRIM5, TRIM6, TRIM22, and TRIM34 genes
We focused our loss of allelic heterozygosity (LOH) analysis on the region spanning TRIM3 by using 6 microsatellite markers in addition to the ones that had been used earlier to determine the minimal area of loss [24]
Summary
Malignant gliomas are frequent primary brain tumors associated with poor prognosis and very limited response to conventional chemo- and radio-therapies. Human Tripartite motif protein 3 (TRIM3) encodes a structural homolog of Drosophila brain tumor (brat) implicated in progenitor cell proliferation control and cancer stem cell suppression. This therapeutic resistance has recently been attributed to tumor stem-like cells due to their unrestrained self-renewal capacity and the ability to maintain tumorigenic potential at the single cell level, thereby evading both resection and radiotherapy [4,5,6,7]. There is growing evidence that some brain cancers arise either from normal stem cells or from progenitor cells in which self-renewal pathways have become aberrantly activated [7,8,9,10]
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