Predictive value of progression-associated chromosomal aberrations for the prognosis of meningiomas: a retrospective study of 198 cases.

OBJECT: The goal of this study was to determine whether in meningiomas cytogenetic findings are suitable as a predictive parameter relevant to prognosis. METHODS: Between 1992 and 1998 at the Department of Neurosurgery, Saarland University, 198 patients underwent surgery to resect meningiomas. The meningiomas were investigated cytogenetically and the patients were followed up for a mean period of 33 months. On the basis of the cytogenetic findings, the meningiomas were subdivided into four groups: Group 0 meningiomas displayed a normal diploid chromosome set; Group 1 tumors were found to have monosomy 22 as the sole cytogenetic aberration; Group 2 tumors were markedly hypodiploid meningiomas with loss of additional autosomes in addition to monosomy 22; and Group 3 meningiomas had deletions of the short arm of a chromosome 1, as well as additional chromosomal aberrations including loss of one chromosome 22. One hundred ninety-eight patients in whom tumor resections were determined to be Simpson Grade I or II could be followed up after complete tumor extirpation. In 20 patients, one or several recurrences were documented during the period of observation. The tumors were classified according to their different, but mostly uniform chromosomal aberrations. Recurrences were found in six (4.3%) of 139 tumors in Groups 0 and 1 and in two (10.5%) of 19 tumors in Group 2; the highest rate of recurrence was found in 12 (30%) of 40 tumors in Group 3. This supports the notion that the deletion of the short arm of one chromosome 1 is an important prognostic factor in meningiomas. The results of this study document a significant correlation between histological grade (p < 0.0001), location (p < 0.0001), and recurrences of meningiomas (p < 0.0001) (significance determined using chi-square tests). CONCLUSIONS: 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.

Deletion of chromosome 1p and loss of expression of alkaline phosphatase indicate progression of meningiomas.

Meningiomas are cytogenetically characterized by loss of one chromosome 22 as a typical primary aberration and progression-associated secondary chromosome changes, of which monosomy 1p is the most common. The aim of this study was to evaluate the significance of monosomy 1p and enzyme activity loss of tissue nonspecific alkaline phosphatase (ALPL), whose gene maps to chromosome 1p36.1-p34, as parameters for the diagnosis of progression-prone meningiomas. We analyzed smear preparations of 56 meningiomas and additional paraffin sections of 17 of the cases by two-color fluorescence in situ hybridization (FISH) using the D1Z1 and D1Z2 probes and by a metaphase cytogenetic analysis of 30 of these tumors. The results were compared to clinical and morphological parameters and the expression of ALPL. Smear preparations showed deletion of 1p36 in 27% of common-type, 70% of atypical (intermediate-type), and 100% of anaplastic meningiomas. Monosomy 1p, as detected by FISH or the karyotype, was strongly associated with complete loss of ALPL activity. Intermediate-type and anaplastic meningiomas of younger patients displayed an increasing rate of cells with trisomy 1q and relative loss of 1p. The highly significant correlation of FISH results and ALPL histochemistry with clinical parameters gives evidence of their strong prognostic relevance. The complete activity loss of ALPL and the immunologically detected loss of ALPL protein in areas of meningiomas with monosomy 1p indicate a cytogenetically undetectable inactivation of the homologous Alpl allele. The apparently homozygous loss of expression of ALPL supports the notion that Alpl is a candidate tumor suppressor gene in meningiomas.

Unbalanced translocation t(1;3)(p12-13;q11) in meningiomas as the unique feature of chordoid differentiation.

Chordoid meningioma is a rare histological subtype of meningiomas. Cytogenetic analysis of three cases revealed the unique feature of an unbalanced translocation der(1)t(1;3)(p12-13;q11) that was ascertained by chromosome microdissection and reverse fluorescence in situ hybridization. As the t(1;3) has not been observed in other subtypes of meningioma, it may represent a specific cytogenetic marker of chordoid meningiomas. It is not yet clear whether a fusion gene or the combined loss of genes from chromosome arms 1p and 3p is the pathogenetically important outcome of the translocation.

Genetic heterogeneity in human astrocytomas: spatial distribution of P16 and TP53 deletions in biopsies.

Smear preparations of 23 fresh astrocytoma biopsies were analyzed by two-color fluorescence in situ hybridization with cosmids specific for the P16 and the TP53 genes. Additionally, tissue sections of the same tumors were immunostained with the use of a monoclonal antibody that recognizes both wild-type and mutant TP53 protein. In 21 astrocytomas, loss of P16 was observed in a significant proportion of cells. Cells with homozygous P16 loss were present in 13 astrocytomas; 14 astrocytomas showed cells with heterozygous loss of P16. Remarkably, 5 astrocytomas showed a scattered mosaic pattern of cells with homozygous and, respectively, heterozygous p16 loss. Homozygous deletion of TP53 was not observed. Cells with heterozygous TP53 loss were detected in 12 tumors, in 7 of them in association with P16 loss. One tumor showed aberrant cells for neither TP53 nor P16 but strong immunostaining for TP53. Positive TP53 immunostaining was found in 16 astrocytomas. Heterozygous loss of TP53 was significantly correlated with TP53 protein expression. We conclude that, unlike typical tumor suppressor genes, P16 might enhance cellular proliferation after heterozygous loss through a dosage effect and that the distribution of cells with homozygous loss of P16 speaks in favor of a polyclonal loss of the second copy of this gene.

Loss of alkaline phosphatase activity in meningiomas: a rapid histochemical technique indicating progression-associated deletion of a putative tumor suppressor gene on the distal part of the short arm of chromosome 1.

Apart from defined histomorphologic features, increased Ki-67 indices and various numeric and structural chromosome aberrations, meningiomas of the intermediate (WHO grade II, atypical meningioma) and anaplastic type (WHO grade III) are cytogenetically distinguished from common-type meningiomas (WHO grade I) by frequent loss of the distal part of the short arm of one chromosome 1 (1p-), which formerly proved to be an independent predictor of shorter recurrence-free intervals. Histochemically, loss of alkaline phosphatase activity (ALPL, liver/bone/kidney type, EC 3.1.3.1) was another frequent, specific finding in meningiomas with signs of dedifferentiation. In a prospective study including 66 meningiomas, all common-type meningiomas except one case (18/19) were reactive for ALPL, whereas 75% (30/39) of intermediate type and all anaplastic meningiomas (8/8) showed loss of enzyme activity in large areas of the tumor. Exclusively, the ALPL negative phenotype was associated with 1p loss (15/19). Our data suggest that ALPL, which is coded as a single copy gene on chromosome 1p36.1-p34, is a useful marker enzyme for the loss of a putative regulatory (tumor suppressor) gene on chromosome 1p, or that ALPL itself represents a new tumor suppressor gene homozygously inactivated in meningiomas.

Early proliferation enhancement by monosomy 10 and intratumor heterogeneity in malignant human gliomas as revealed by smear preparations from biopsies.

We performed simultaneous fluorescence in situ hybridization (FISH) with centromere-specific DNA probes for chromosomes 7 and 10 and Ki-67 proliferation labelling on smear preparations of 17 differentiated and anaplastic human astrocytomas and glioblastomas. In 15 of the 17 cases studied, Ki-67-positive clones differed from Ki-67-negative clones mainly by the loss of one copy of chromosome 10, either combined with or independent of trisomy 7. The findings suggest that monosomy 10 is an earlier event than generally supposed in the development of human gliomas and that it is directly related to cellular hyper-proliferation.

A novel site of DNA amplification on chromosome 1p32-33 in a rhabdomyosarcoma revealed by comparative genomic hybridization.

Cytogenetic analysis of a human embryonal rhabdomyosarcoma revealed a near-diploid karyotype with structural chromosome aberrations not involving the typical rearrangements of rhabdomyosarcomas, plus a large number of double minutes. Comparative genomic hybridization revealed a previously undescribed site of DNA amplification on the short arm of chromosome 1 (band 1p32-33).