By screening a meningioma expression library with autologous serum we identified four cDNA clones representing a novel gene with striking homology to Caenorhabditis elegans hyaluronidase as indicated by BLASTP analysis. In humans hyaluronidase has been implicated in cancer development and three human genes are known to encode proteins with hyaluronidase activity. None of the human genes, however, showed any homology at the nucleotide or amino acid sequence level to the newly isolated antigen we termed meningioma expressed antigen 5 (MGEA5). Somatic cell hybrid mapping and fluorescence in situ hybridization mapped the gene for MGEA5 to chromosomal band 10q24.1-q24.3. Reverse transcription (RT)-PCR and northern blot hybridization revealed expression of the gene encoding MGEA5 in several meningioma and additional human tissues. Expression analysis also indicated an alternative splicing event giving rise to a shorter and altered transcript termed MGEA5s. The expression of MGEA5 and MGEA5s as fusion proteins revealed an approximate molecular weight of 92 and 54 kDa, respectively. Using heterologous sera we found antibodies against MGEA5s in five out of 23 meningioma patients, whereas no immune reaction was detected in 12 control sera from healthy individuals. Confirmation of hyaluronidase activity was independently achieved by turbidometric analysis and a gel matrix assay. A model for involvement of the novel hyaluronidase gene in meningioma development is proposed.

The cytogenetic classification of meningiomas provides a significant contribution to the predictability of tumor recurrence and is, therefore, a valuable criterion for the neurosurgeon's postoperative management protocol.

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The term "multiforme" in glioblastoma multiforme (GBM) indicates the highly variable histomorphology that cannot be addressed by studies on homogenized tissue probes. In order to relate genetic findings with histomorphologically distinct areas we used microdissection to procure defined cell populations from microscopic tissue sections under direct visualization. Formalin-fixed and paraffin-embedded tissue sections of 10 GBM were evaluated for intratumoral genetic heterogeneity by microdissection of multiple areas of 20-50 tumor cells and DOP-PCR of DNA isolated from the dissected cell groups, followed by comparative genomic hybridization (CGH). Microdissected cells from histomorphologically normal extratumoral blood vessels from the same slides served as controls. The individual tumors showed variable combinations of primary chromosomal gains and losses common to all studied areas of a given case along with secondary, area-specific additional aberrations. CGH displayed a wider variety of chromosomal aberrations than metaphase cytogenetics of cell cultures from the same tumors. The most frequent aberrations observed were previously unperceived gains on chromosomes 4q (8/10) and 5q (5/10). Other nonrandom aberrations were gains on 12q (6/10), 13q (6/10), and 7 (5/10), and losses of 22 (5/10). Amplifications on 7p were intratumorally heterogeneous and only found in single areas of 2 tumors. In contrast to normal extratumoral vessels, vascular proliferates in most cases demonstrated chromosomal aberrations (CGH) which were partially different from the aberrations observed in the tumor itself. The described method gives evidence of considerable intratumoral genetic heterogeneity in GBM and provides a sensitive tool for the detection of quantitative chromosomal changes that are present only regionally within a given tumor.

Meningiomas are mostly benign tumors that originate from the coverings of brain and spinal cord. Typically, they reveal a normal karyotype or monosomy for chromosome 22. Rare clinical progression of meningiomas is associated with a nonrandom pattern of secondary losses of other autosomes. Deletion of the short arm of one chromosome 1 appears to be a decisive step for anaplastic growth in meningiomas. We calculated an oncogenetic tree model that estimates the most likely cytogenetic pathways of 661 meningioma patients in terms of accumulation of somatic chromosome changes in tumor cells. The genetic progression score (GPS) estimates the genetic status of a tumor as progression in the corresponding tumor cells along this model. Large GPS values are highly correlated with early recurrence of meningiomas [p < 10 24 ]. This correlation holds even if patients are stratified by WHO grade. We show that tumor location also has an impact on genetic progression. Clinical relevance of the GPS is thus demonstrated with respect to origin, WHO grade and recurrence of the tumor. As a quantitative measure the GPS allows a more precise assessment of the prognosis of meningiomas than categorical cytogenetic markers based on single chromosomal aberrations. ' 2007 Wiley-Liss, Inc.