Interstitial loss and gain of sequences on chromosome 22 in meningiomas with normal karyotype

In nearly half of sporadic low grade meningiomas no chromosome aberration can be detected. In the majority of the other half chromosome 22 is lost. In higher grade meningiomas this loss is followed by characteristic secondary chromosome aberrations. Regarding the molecular findings in Schwannomas, homozygous loss or mutation of the NF2 gene located on chromosome 22, was supposed also to be the primary event in meningioma development. However, in nearly all high grade but in only a minority of low grade meningiomas the loss of the NF2 protein is observed. Therefore, both the hypothetical combined heterozygous loss of or inactivation of two or more tumour suppressor genes (at least one of them located on chromosome 22) or the homozygous loss of a regulatory gene on chromosome 22 different from NF2 was discussed. In search for microdeletions or/and structural recombinations of chromosome 22 we investigated primary cell cultures of 43 meningiomas by conventional G-banding (26 without, 17 with loss of chromosome 22). Twenty-seven tumours were analysed with spectral karyotyping (SKY) and 16 with fluorescence in situ hybridisation (FISH) with DNA probes for the chromosomal regions of 22q11.2, 22q11.23q12.1, 22q12.1 and 22q13.3. SKY analysis confirmed G-banding data for chromosome 22 and could specify marker chromosomes and translocations containing material from chromosome(s) 22. Confirming our assumption microdeletions on chromosome 22 were detected by FISH in 6/8 cytogenetically non-aberrant meningiomas. Surprisingly, in 2/8 cases we observed gains of the 22q13.3 and in 2/8 gains of the 22q12.1 region. Here we present first evidence for an uncommon mechanism during early meningioma development at least for a meningioma subgroup: i) duplication and translocation of sequences from chromosome 22 to different chromosomes. ii) deletion of the original sequences on chromosome 22, resulting in disomy again (only visible as translocation in metaphase FISH). iii) loss of chromosome 22.     

Frequent Loss of 1p32 Region but no Mutation if the p18 Tumor Suppressor Gene in Meningiomas

After chromosome 22 and NF2 inactivation, the loss of chromosome 1p is one of the most frequent abnormalities encountered in meningiomas. However the putative tumor suppressor gene located on 1p inactivated in meningiomas has still to be identified. We screened 68 meningiomas for LOH on chromosome 22 and 1. We found 34 LOH on the NF2 region on chromosome 22 (50%) and 19 LOH on 1p (28%), 16 being associated with loss of chromosome 22. Partial deletions delimited a candidate region located between D1S234 and D1S2797. The p18 ^INK4C tumor suppressor gene, a member of the genes family coding for inhibitors of cyclin-dependent kinases, is located in this region. To determine whether p18 is involved in development of meningiomas, we performed a mutation analysis of the p18 gene and a search for homozygous deletion in the 19 meningiomas with 1p loss. Sequencing analysis of the p18 gene revealed one polymorphism, but no somatic mutations and no homozygous deletions were found. These results confirm that the loss of chromosome 1p32 is a frequent feature in meningiomas, however the p18 tumor suppressor gene which is located in this region, does not seem to be involved.     

Molecular and genetic profiles of radiographically defined de novo meningiomas

With the exception of radiation-induced tumors, benign meningiomas that are known to have developed within a defined time period are extremely rare. We have genetically characterized two cases of radiographically defined de novo, sporadic meningiomas—a 5-cm, left parasagittal tumor in a 61-year-old male and a 2.3-cm, right falx tumor in a 53-year-old female. Neither tumor was observed during MRIs performed for unrelated complaints 49 and 28 months before surgery, respectively. Both tumors were totally resected, and histopathological examination revealed WHO grade I meningiomas. In both cases, the MIB-1 staining indices were high for grade I meningioma (5.6% for case 1 and 9.1% for case 2), and abnormal accumulation of p53 were observed by immunohistochemistry. The two tumors shared losses of chromosome arms 1p and 7p by comparative genomic hybridization. The tumor suppressor merlin, product of the NF2 gene, was not detected in either tumor. These abnormalities found in common in both of the de novo meningiomas likely to play significant roles in the pathogenesis and/or rapid development of meningiomas. Moreover, taken together with previous studies, our findings indicate that the combined loss of 1p and 7p may play a critical role in the tumorigenesis of de novo, aggressive meningiomas.     

NF2 gene mutations and allelic status of 1p, 14q and 22q in sporadic meningiomas.

Formation of meningiomas and their progression to malignancy may be a multi-step process, implying accumulation of genetic mutations at specific loci. To determine the relationship between early NF2 gene inactivation and the molecular mechanisms that may contribute to meningioma tumor progression, we have performed deletion mapping analysis at chromosomes 1, 14 and 22 in a series of 81 sporadic meningiomas (54 grade I (typical), 25 grade II (atypical) and two grade III (anaplastic)), which were also studied for NF2 gene mutations. Single-strand conformational polymorphism analysis was used to identify 11 mutations in five of the eight exons of the NF2 gene studied. All 11 tumors displayed loss of heterozygosity (LOH) for chromosome 22 markers; this anomaly was also detected in 33 additional tumors. Twenty-nine and 23 cases were characterized by LOH at 1p and 14q, respectively, mostly corresponding to aggressive tumors that also generally displayed LOH 22. All three alterations were detected in association in seven grade II and two grade III meningiomas, corroborating the hypothesis that the formation of aggressive meningiomas follows a multi-step tumor progression model.     

Loss of heterozygosity on chromosome 22q and 17p correlates with aggressiveness of meningiomas

According to reported cytogenetic studies, there is a significant association between chromosomal aberrations and aggressiveness in meningiomas. With the method of restriction fragment length polymorphism analysis (RFLP), we examined tumor specific LOH on chromosome 17p and 22q in 30 cases of intracranial meningiomas. There were eight cases of meningiomas with aggressive characteristics, such as invasive meningioma, malignant meningioma, hemangiopericytic meningioma, and multiple meningiomas with central neurofibromatosis. Twenty-five of 30 cases (83%) were constitutionally heterozygous for at least one of the chromosome 22q DNA markers and sixteen of 25 informative cases (64%) displayed loss of heterozygosity (LOH). All of the 8 informative cases (100%) of meningiomas with aggressive characteristics, showed LOH on chromosome 22q whereas non-aggressive cases revealed LOH in eight of 17 informative cases (47%). At the loci on chromosome 17p, only two cases of malignant meningionas showed LOH. Our results suggest that the inactivations of putative tumor suppressor genes on chromosome 22q and 17p may correlate with aggressiveness and malignant transformation of meningiomas.     

Evidence for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.

Previous studies have shown frequent allelic losses of chromosomes 9p, 10, 17p, and 22q in glial tumors. Other researchers have briefly reported that glial tumors may also show allelic losses of chromosome 19, suggesting a putative tumor suppressor gene locus on this chromosome (D. T. Ransom et al., Proc. Am. Assoc. Cancer Res., 32:302, 1991). To evaluate whether loss of chromosome 19 alleles is common in glial tumors of different types and grades, we performed Southern blot restriction fragment length polymorphism analysis for multiple chromosome 19 loci in 122 gliomas from 116 patients. Twenty-nine tumors had loss of constitutional heterozygosity of 19q, and four tumors had partial deletions of 19q. Allelic losses on 19q were restricted to grade III anaplastic astrocytomas (4/9) and grade IV glioblastomas (11/46), grade II oligodendrogliomas (2/5) and grade III anaplastic oligodendrogliomas (2/2), and grade II (5/8) and grade III (5/7) mixed oligoastrocytomas. These data demonstrate genetic similarities between astrocytomas, oligodendrogliomas, and mixed glial tumors and indicate the presence of a glial tumor suppressor gene on chromosome 19q.     

Alternative Splicing of CHEK2 and Codeletion with NF2 Promote Chromosomal Instability in Meningioma

Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors. In aggressive meningiomas, 22q deletions are generally accompanied by the presence of large-scale segmental abnormalities involving other chromosomes, but the reasons for this association are unknown. We find that large-scale chromosomal alterations accumulate during meningioma progression primarily in tumors harboring 22q deletions, suggesting 22q-associated chromosomal instability. Here we show frequent codeletion of the DNA repair and tumor suppressor gene, CHEK2, in combination with NF2 on chromosome 22q in a majority of aggressive meningiomas. In addition, tumor-specific splicing of CHEK2 in meningioma leads to decreased functional Chk2 protein expression. We show that enforced Chk2 knockdown in meningioma cells decreases DNA repair. Furthermore, Chk2 depletion increases centrosome amplification, thereby promoting chromosomal instability. Taken together, these data indicate that alternative splicing and frequent codeletion of CHEK2 and NF2 contribute to the genomic instability and associated development of aggressive biologic behavior in meningiomas.     

Diagnostic and prognostic significance of genetic regional heterogeneity in meningiomas

We analyzed the frequency and regional distribution of cells with genetic abnormalities of chromosomes 1, 14, and 22 in meningiomas. This data was evaluated for correlation to the clinical outcome of the patients. Eight defined areas of each of 77 paraffin-embedded meningioma samples (59 grade I, 13 grade II, and 5 grade III) were analyzed by fluorescent in situ hybridization using bacterial artificial chromosome probes localized to chromosomes 1p36.32, 1q25.3, 14q13.3, 14q32.12, 22q11.2, and 22q12.1-3. Chromosome deletion was considered to be regionally heterogeneous if 7 regions showed cells with chromosome deletions. Deletion of 1p occurred in 35% of the grade I tumors. Distribution of cells with 1p deletion was regionally heterogeneous in 25% and homogeneous in 10% of grade I tumors. Distribution of cells with deletion of 1p was regionally heterogeneous in 23% and homogeneous in 69% of the grade II tumors. All grade III meningiomas had homogeneous distribution of cells with deletion of chromosome 1p. Distribution of cells with deletion of 14q was regionally heterogeneous in 27% and homogeneous in 2% of the grade I meningiomas, heterogeneous in 31% and homogeneous in 62% of the grade II tumors, and heterogeneous in 40% and homogeneous in 60% of the grade III meningiomas. Distribution of cells with deletion of 22q was regionally heterogeneous in 15% and homogeneous in 3% of the grade I tumors, heterogeneous in 15% and homogeneous in 31% of grade II tumors, and homogeneous in 20% of the grade III meningiomas. Distribution of cells with trisomy 22q was regionally heterogeneous in 10% of grade I tumors, heterogeneous in 23% of grade II, and homogeneous in 80% of grade III meningiomas. The proportion of patients with a deletion of 22q (either homogeneous or heterogeneous) who had recurrence was greater than the proportion of those without 22q deletion who had recurrence, and deletion of 22q was significantly associated with radiologically detected recurrence (P < 0.05). We conclude that the appearance of chromosomal aberrations in different areas of the tumor demonstrates the importance of regional heterogeneity in the biological behavior of meningiomas.     

Place des méningiomes dans les tumeurs du système nerveux central au centre hospitalier universitaire Yalgado Ouédraogo (CHU-YO) de Ouagadougou : approche histopathologique

Background

Worldwide there are varying reports on the prevalence of meningiomas among central nervous system neoplasms. Different reports state meningiomas, gliomas, or metastatic tumors as the most common tumors among central nervous system neoplasms. The aim of our study was to determine the relative frequency of meningiomas among central nervous system neoplasms in our environment.

Method

Consecutive patients (86) seen at Neurosurgery Office of Yalgado Ouédraogo Teaching Hospital of Ouagadougou, with histologically proven central nervous system tumor over a 7 years period (2005–2011), were retrospectively analyzed.

Results

The commonest histological types were meningiomas, gliomas, metastasis, and pituitary tumors. Thirty-one patients (36.04%) had histologically confirmed meningioma during the study period, 25 (29.07%) had glioma, 6 (7.33%) had metastasis, and 5 (5.81%) had pituitary adenoma. The mean age of the 86 patients was 37.05 years, with 55.61% of male. The mean age of the meningiomas cases was 45.32, with 61.3% of female. 90.31% had grade I meningioma.

Conclusion

The study showed that meningioma is the most common tumor among central nervous system neoplasms in our environment, with a predominance of grade I meningothelial sub-type.     

Chromosomal and genetic aberrations differ with meningioma subtype

Meningioma is one of the most common brain tumors, and a variety of genetic abnormalities have been detected by the Southern blotting, polymerase chain reaction (PCR), fluorescence in situ hybridization (FISH), and comparative genomic hybridization (CGH) methods. However, these methods detect only a very limited portion of the tumor genome or have a limited mapping resolution. In this study, we used DNA microarray assay, which detects numerous genetic abnormalities and analyzes a global assessment of molecular events in tumor cells. We analyzed genomic DNA from 26 patients with benign meningiomas by GenoSensor Array 300 in order to characterize gene amplifications, gene deletions, and chromosomal information in the whole genome. Loss of chromosome 22q was found most frequently. This chromosomal aberration was detected in 14 meningiomas (53.8%), particularly in transitional and fibrous meningiomas. In meningothelial meningiomas, amplification ofINS andTCL1A was detected more frequently than in other meningioma subtypes. DNA microarray assay revealed new genetic differences among the meningioma subtypes, thus indicating that this novel technique is useful for understanding tumor genesis and for the diagnosis of meningioma subtype.     

Refinement and distinction of the chromosome 10p candidate tumor suppressor region in human gliomas

Our recent studies have shown that telomeric 10p is frequently deleted in both low and high grade gliomas. Other studies have shown an invariant association of erb-b amplification and loss of chromosome 10. It has not been determined whether this association was specific for a particular locus on chromosome 10. We sought to assess this by examining tumors, for both 10p loss and gene amplification. 55% of tumors showed some degree of allelic imbalance at 10p15. Amplification of erb-b, c-myc, and a mitochondrial cDNA probe, recently found to be amplified in diverse grades of gliomas was assessed. erb-b and the mitochondrial cDNA probe showed amplification in 28% of the tumors; c-myc gene was amplified in only one astrocytoma. No significant association was noted when comparing the presence of a specific amplified gene, and loss of loci on chromosome. Chromosome 10p15 shows significant loss in glial tumors, and is independent of the chromosome 10 region associated with erb-b amplification. The region at 10p15 is distinct in harboring a putative tumor suppressor gene in gliomas, and is involved earlier in the multi-step pathway to glial tumor malignancy.     

Exon scanning for mutations of the nf2 gene in pediatric ependymomas,rhabdoid tumors and meningiomas

Deletions of chromosome 22 have been identified in 3 types of childhood primary brain tumor: meningiomas, rhabdoid or atypical teratoid tumors (ATT) and ependymomas. This implicates the involvement of tumor suppressor genes on chromosome 22 in the genesis of these rare tumors. One such candidate tumor suppressor gene is the recently cloned neurofibromatosis 2 (NF2) locus. The purpose of our study was to determine the frequency of germ-line and somatic NF2 mutations in a selected group of brain tumors in children. Using single-strand conformation polymorphism (SSCP) assays we screened 17 exons of the NF2 gene in 13 pediatric brain tumors and 9 matched normal blood DNA samples. Tumors included 3 meningiomas, 2 rhabdoid or ATTs, 7 ependymomas and 1 malignant tumor of glial lineage. In addition, lymphoblastoid cell lines from 3 patients with rhabdoid/ATT in whom no tumor tissue was available were analyzed for germ-line mutations. Migration shifts were not detected in any of the normal DNA samples analyzed. Of the 13 tumors screened by SSCP, 1 meningioma with monosomy 22 produced a migration shift in exon 13. DNA sequencing of exon 13 revealed a deletion of a single guanine nucleotide (base 1397) in codon 466, causing a frame shift. While not all mutations might have been picked up by this technique, the data suggest that, similar to adult sporadic meningiomas, some pediatric meningiomas may result from somatic mutations in the NF2 gene. For rhabdoid tumors and ependymomas it appears that a locus distinct from NF2 might be responsible for tumorigenesis. © 1995 Wiley-Liss, Inc.     

Multiple meningiomas: Investigating the molecular basis of sporadic and familial forms

Meningiomas are common tumors of the coverings of the central nervous system (CNS), comprising 20% of intracranial neoplasms. The only genes known to be associated with sporadic meningiomas are NF2 on chromosome 22 and the related cytoskeleton element DAL-1 on chromosome 18. Between 1 and 8% of patients with meningiomas develop multiple meningiomas, a trait transmitted occasionally in an autosomal dominant fashion. We investigated the DAL-1 and NF2 loci in 7 unrelated multiple meningioma patients without clinical evidence of NF2 by mutational and pathological analysis. Five novel intragenic microsatellite polymorphisms were developed for specific detection of loss of heterozygosity (LOH) at the DAL-1 locus. Three of 7 patients had affected relatives and all affected individuals were female. No tumors from familial patients were of a fibroblastic subtype. Truncating NF2 mutations were detected in 3 tumor specimens, but were not present in the corresponding blood samples. Two tumors showed LOH at the NF2 locus. All tumors showing mutations at the NF2 locus originated from patients without affected relatives and were of the fibroblastic subtype. Five non-truncating alterations in the DAL-1 gene were found, however, LOH of chromosome 18 markers was not seen in any tumor. In contrast to the NF2 results, all DAL-1 alterations were found in paired blood specimens. Our findings provide further evidence that the molecular basis of sporadic and familial multiple meningiomas is fundamentally different and extend this dichotomy to pathologic subtypes. DAL-1 does not function as a true tumor suppressor in these patients.     

Deletion mapping of the long arm of chromosome 22 in human meningiomas

Cytogenetic and molecular genetic analyses have shown that a tumor-suppressor gene for human meningioma is located on the long arm of chromosome 22. Recently, somatic mutations of the NF2 gene have been identified in sporadic meningiomas. However, tumorigenesis of certain cases of meningioma cannot be fully explained by inactivation of the NF2 gene alone. Thus, to obtain some indication as to the existence of another tumorsuppressor gene, it seemed important to re-examine the loss of heterozygosity (LOH) on 22q in sporadic meningioma. A total of 46 sporadic meningiomas was examined for LOH at 20 loci on 22q. LOH was observed in 29 tumors (63%), of which 13 (28%) showed different patterns of a partial loss of 22q. However, the NF2 locus was retained in one tumor that lost a more distal part of 22q. Moreover, 27 of the 28 tumors which showed LOH at the NF2 locus also lost alleles at more telomeric loci. These results raise the possibility that another tumor-suppressor gene for meningioma may exist on 22q and that its localization may be distal to the D22S102 locus. © 1995 Wiley-Liss, Inc.     

Allelic loss at 1p and 19q frequently occurs in association and may represent early oncogenic events in oligodendroglial tumors

The molecular mechanisms underlying the genesis and progression of oligodendroglial tumors are poorly understood, since only restricted information on loss of heterozygosity from isolated cases is available. The commonest alterations appear to involve deletion of 1p and 19q, while loss of heterozygosity for 9p, chromosome 10 or epidermal growth factor receptor gene amplification have been described in single tumors. We have applied restriction fragment length polymorphism analysis to 14 loci covering chromosome 1 and 7 loci on chromosome 19 in a series of 25 tumors with an oligodendroglial component to determine precisely the participation of these suppressor genes in the genesis of tumors. Twenty-two and 19 of the 25 samples displayed LOH at 1p and 19q, respectively, and both anomalies were detected in association in 17 samples, including low- and high-grade oligodendrogliomas as well as mixed oligo-astrocytomas. Our findings suggest that inactivation of tumor suppressor genes located on 1p and 19q represent cooperative alterations occurring at early stages of oncogenic transformation of oligodendroglial neoplasms. © 1995 Wiley-Liss, Inc.     

Cytogenetic and molecular abnormalities in astrocytic gliomas (Review)

In recent years, there have been great advances in our understanding of the genetic events and the molecular biology of human brain gliomas. Cytogenetic information has suggested that a pattern of non-random abnormalities involving numerical deviations such as the gain, partial deletion, or total loss of chromosomes as well as translocations and structural rearrangements of certain chromosome lesions are characteristic features for some tumors. In addition, the somatic activation of cellular oncogenes and inactivation of tumor suppressor genes represent important genetic alterations leading to progressive disorder of normal cellular growth control mechanisms. This review describes the abnormal chromosomal and molecular abnormalities that occur during formation of brain tumors of astrocytic origin, particularly fibrillary astrocytic neoplasms. The most frequent genetic alterations include inactivation of the p53, p16, Rb and PTEN genes, and overexpression of the CDK4, EGFR and VEGF genes. Other less well defined abnormalities include aberrations in chromosomes 1, 9, 10, 11, 19 and 22.     

INI1 mutations in meningiomas at a potential hotspot in exon 9

Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.     

A region of common deletion in 22q13.3 in human glioma associated with astrocytoma progression

Loss of heterozygosity for chromosome 22 (LOH 22) occurs in gliomas of all malignancy grades. Neurofibromatosis type 2 (NF2) patients are at increased risk of developing a glioma. However, the NF2 gene in 22q12.2 is not involved in glioma tumorigenesis. To detect additional regions on chromosome 22 that may harbor tumor suppressor genes important in glioma tumorigenesis, we determined LOH 22 profiles for 159 gliomas using 32 markers. LOH 22 was found in 46 tumors (29%). Thirteen tumors displayed partial LOH 22, from which we deduced a region of common deletion between markers D22S928 and D22S1169 in 22q13.3. LOH of at least this region was detected in 13% of the astrocytomas (As), in 20% of the anaplastic astrocytomas (AAs) and in 35% of the glioblastomas multiforme (GBMs). The significant increased frequency of LOH 22q13.3 in the highest malignancy grade (GBM vs. A and AA, p = 0.02) indicates that loss of this region is associated with astrocytoma progression.     

Deletion mapping of chromosome 19 in human gliomas

There is evidence that a putative glioma tumor suppressor locus resides on the long arm of chromosome 19. We present data on 161 gliomas from IS6 patients, which were studied by microsatellite analysis for loss of heterozygosity (LOH) on chromosome 19. Eight loci on the long arm and 2 loci on the short arm of chromosome IV were examined. LOH on I9qwas observed in 3/19 astrocytomas (WHO grade II), 12/27 anaplastic astrocytomas (WHO grade III), 16/76 cases of glioblastoma multiforme WHO (grade IV), 4/9 oligodendrogliomas (WHO grade II), 3/5 anaplastic oligodendrogliomas (WHO grade III), 5/9 mixed oligo-astrocytomas (WHO grade II) and 8/10 anaplastic oligo-astrocytomas (WHO grade III). While 31 of the tumors with LOH on chromosomal arm I9q exhibited allelic loss at every informative locus, 20 tumors showed terminal or interstitial deletions. In contrast to astrocytomas and glioblastomas, tumors with an oligodendroglial component had predominantly lost the entire long arm of chromosome 19. The common region of overlap in gliomas was located on 19q 13.2-q 13.4 between the markers D 19S 178 and D 19S 180. Our data confirm the involvement of a putative tumor suppressor gene on chromosomal arm 19q in gliomas and assign this gene to 19q 13.2-q 13.4.