Charakterisierung molekulargenetischer Prognosefaktoren auf dem kurzen Arm des Chromosoms 1 in humanen Meningeomen.

Meningiomas are slowly growing benign tumors of the central nervous system. In some cases they represent a diagnostic and therapeutic challenge: grading of atypical and anaplastic tumors by histopathological patterns can be difficult in spite of the modified WHO-classification. On the other hand the high recurrence rate of benign meningiomas can be a problem. Histological and clinical criteria predicting recurrence rate and malignant transformation are not well defined yet. For this reason molecular predictors became more important. Partial or complete loss of one chromosome 22 is known as the most common chromosome aberration in meningiomas and represents the decisive step to induce tumoral growth. Secondary loss of genomic sequences (LOH) on the short arm of chromosome 1 (1p) seems to be more frequent in atypical and anaplastic tumors and is discussed as a prognostic marker of malignancy in meningiomas. Aim of the present study was to evaluate molecular predictors of aggressive clinical behaviour by performing a transcriptional analysis of 1p specific genes. To confirm the results gained on mRNA level a LOH study and analysis of protein expression (western blot) was performed. In addition, immunohistochemical expression of tissue unspecific alkaline phosphatase (ALPL) was analysed to confirm the molecular genetic results by a rapid and practicable method. On transcriptional level accumulation of expression deficits was discovered in the genomic region of the genes ALPL, RAB3B and GADD45. A region of frequent genomic alterations could be defined, but no single candidate gene. Accumulation of transcriptional deficits on chromosome 1p in atypical and anaplastic tumors supported the biological meaning of 1p loss in meningioma progression as reported in the literature. The detected high correlation between loss of sequences on 1p and tumor progression in meningiomas was confirmed by the results of the LOH study. Correlation between ALPL-mRNA-expression and ALPL-protein-expression emphasised the hypothesis of genetic alterations in coding sequences during tumor progression. Immunohistochemistry for ALPL supplied evidence that the progression associated ALPL loss is well detectable by this practicable technique. Concerning RAB3B there were divergent results indicating complex regulatory mechanisms. Because of one intact allele heterozygous loss (LOH) of TSG is not expected to result in complete loss of mRNA expression. In the present study the second allele is assumed to be inactivated, the mechanism of inactivation is not yet explained. A possible explanation is Knudson’s two-hit model that could be postulated but not proven in meningiomas. Probably the complete inactivation is not effect of microdeletion or mutation, but a complex regulatory effect. The predictive value of 1p-deletions for aggressive clinical behaviour in meningiomas could be confirmed in the present study. If it would be possible to use this prognostic relevant parameter in clinical routine, particular patients with recurrent or malignant meningiomas could profit.