Abstract:Background The most common chromosomal aberration found in meningiomas is monosomy 22. Progression and recurrence of meningiomas are usually associated with additional chromosome losses. Rarely, however, meningiomas have strongly hyperdiploid karyotypes with over 50 chromosomes; the objective of this study was to explore the cytogenetic and histopathologic patterns as well as the clinical significance of hyperdiploidy in meningiomas. Methods Within a series of 677 consecutive meningiomas, we identified a subgr… Show more
“…The association between NF2 mutation and chr22 loss extended to the validation and extrapolation sets (p<0.0001) and confirms prior reports using other methods 16 . In the grade I tumors, we also found recurrent significant losses on 1p, 7p, 14p, and 19 and gains on chr5 and chr20 (q<0.1), some of which have been described previously 17 . Higher-grade tumors of the extrapolation set exhibited additional recurrent losses on 10q and 14q, previously reported in atypical and anaplastic meningiomas 1 .…”
Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
“…The association between NF2 mutation and chr22 loss extended to the validation and extrapolation sets (p<0.0001) and confirms prior reports using other methods 16 . In the grade I tumors, we also found recurrent significant losses on 1p, 7p, 14p, and 19 and gains on chr5 and chr20 (q<0.1), some of which have been described previously 17 . Higher-grade tumors of the extrapolation set exhibited additional recurrent losses on 10q and 14q, previously reported in atypical and anaplastic meningiomas 1 .…”
Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
“…Structural aberrations are rare, except for the loss of the short arm of one chromosome 1, which appears to be the decisive step for anaplastic growth [3], [4], [19]–[27].…”
Meningiomas are tumors that arise from the coverings of the brain or spinal cord. 5% of the cases turn into malignant forms with aggressive clinical behavior and increased risk of tumor recurrence. One hundred and five patients with meningiomas were operated by open surgery. To investigate predictors of meningioma recurrence in total 124 samples of 105 patients were investigated by iFISH. Dual-probe hybridization was performed to access chromosomal alterations of chromosomes 1p-, 9p- and 22q. Additionally, methylation of TIMP3 and p16 was analyzed with MS-PCR. Of the 105 investigated tumors 59.1% (62/105) were WHO grade I, 33.3% (35/105) were WHO grade II and 7.7% (8/105) were anaplastic meningiomas (grade III), respectively. The histopathological data correlates with the recurrence rate of the investigated meningiomas. Hypermethylation of TIMP3 was detected in 13.3% of all meningiomas: 10.9% in WHO grade I meningiomas, 25.0% in grade II and 14.3% in grade III meningiomas, respectively. No correlation of TIMP3 hypermethylation with tumor recurrence or WHO grade (p = 0.2) was observed. Interestingly, deletion of 1p36 emerged as a significant predictor of shorter overall survival (log rank test, p<0.001), whereas TIMP3 promoter methylation had no significant effect on overall survival (log rank test, p = 0.799). The results of the current study support the finding that the deletion of chromosome 1p is an independent marker of meningioma recurrence and progression (p = 0.0097). Therefore the measurement of genetic aberrations in meningiomas allows in a combined histological approach a more precise assessment of the prognosis of meningiomas than histopathology alone.
“…Since 1967 cytogenetic analyses have been widely used to understand origin and course of the disease in meningiomas (17). Until now cytogenetic analyses show that numerical and structural chromosome changes with pronounced hypodiploidy, very rarely hyperdiploidy, and especially deletion of the short arm of a chromosome 1, are accompanied by more aggressive biological characteristics (2,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35).…”
Section: Discussionmentioning
confidence: 99%
“…Although more homogeneous than other tumor types, meningiomas show considerable intratumoral cytogenetic heterogeneity, particularly in their anaplastic form (20,21,23,24,29,31,32,(43)(44)(45). These findings raise the question which of the cytogenetic findings is responsible for the further clinical course and the biological behavior of the meningioma.…”
Section: Discussionmentioning
confidence: 99%
“…Hypodiploidy without monosomy 22 is very rare. Typically, the loss of chromosome 22 (17-19) is followed by the loss of additional complete chromosomes or parts of them, in particular loss of one chromosomes 6, 10, 14, 18, and 19, and partial or complete loss of the short arm of one chromosome 1 (2,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Increasing hypodiploidy is strongly correlated with increasing histological grade.…”
Abstract. Meningiomas arise from the coverings of the brain or the spinal cord. They are mostly benign and can be surgically cured. However, in approximately 5% of the cases, they turn into malignant forms with aggressive clinical behavior and increased risk of tumor recurrence. Cytogenetically meningiomas are well characterized, with normal karyotype or monosomy of chromosome 22 in most tumors and clinically relevant secondary losses of other autosomes and sex chromosomes in a subset of anaplastic tumors. Statistical analyses were performed for 1064 karyotypes derived from 661 meningiomas with respect to progression, and recurrence of the tumor. The order of accumulating genetic aberrations has previously been biostatistically estimated with oncogenetic tree models, and a genetic progression score derived from these models was shown to be predictive for tumor recurrence. Although more homogeneous than other cancer types, meningiomas show considerable intratumoral cytogenetic heterogeneity, particularly in their anaplastic form. We observed different cytogenetic patterns in tumor cells of 224 out of 661 (33.4%) meningiomas. The present study demonstrates that it is not sufficient to consider only the most frequent cytogenetic pattern observed in a sufficient set of cells derived from the same tumor. Even a single cell with more advanced genetic progression may start a clone and indicates also clinical progression. Cox regression analysis reveals that the clone with most advanced progression is a leading marker for recurrence in meningiomas. The aim of this study was the analysis of genetic heterogeneity on single cell basis. Further we investigated if there is a substantial correlation between the intratumoral heterogeneity of a given meningioma and its recurrence risk. We were able to show that the selection of single genetically advanced cells improves the prediction of clinical meningioma progression in a more precise manner.
IntroductionMeningiomas are almost always sporadic and rarely multiple tumors of the brain (1). In their sporadic form, they are typically benign and grow slowly. They appear mostly in the later decades of life. According to a study comprising 661 tumors (2), more than 75% of meningiomas belong to the common type (WHO grade I), ~20% belong to the atypical or intermediate type (WHO grade II) and only ~3% belong to the anaplastic type (WHO grade III). Anaplastic meningiomas and a minority of common and intermediate type meningiomas are characterized by aggressive clinical behavior with increased risk of tumor recurrence. However, meningiomas show an unexpectedly high recurrence rate (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15).Between 30 and 60% of meningiomas have a normal karyotype within the tumor cells. Loss of one chromosome 22 is known to be a primary event, but it is difficult to provide evidence for the homozygous loss of a tumor suppressor gene on this chromosome. Approximately 25% of the meningiomas show monosomy 22 as the only aberration in the vast majority of cells. Hypodiplo...
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