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NF2 Alteration/22q Loss Is Associated with Recurrence in WHO Grade 1 Sphenoid Wing Meningiomas.

ABSTRACT: Sphenoid wing meningiomas account for 11-20% of all intracranial meningiomas and have a higher recurrence rate than those at other sites. Recent molecular biological analyses of meningiomas have proposed new subgroups; however, the correlation between genetic background and recurrence in sphenoid wing meningiomas has not yet been fully elucidated. In this study, we evaluated the clinical characteristics, pathological diagnosis, and molecular background of 47 patients with sphenoid wing meningiomas. Variants of NF2, AKT1, KLF4, SMO, POLR2A, PIK3CA, TRAF7, and TERT were determined using Sanger sequencing, and 22q loss was detected using multiplex ligation-dependent probe amplification. Alterations were localized at NF2 in 11 cases, had other genotypes in 17 cases, and were not detected in 12 cases. Interestingly, WHO grade 1 meningiomas with NF2 alteration/22q loss (p = 0.008) and a MIB-1 labeling index > 4 (p = 0.03) were associated with a significantly shorter recurrence-free survival, and multivariate analysis revealed that NF2 alteration/22q loss was associated with recurrence (hazard ratio, 13.1). The duration of recurrence was significantly shorter for meningiomas with NF2 alteration/22q loss (p = 0.0007) even if gross-total resection was achieved. Together, these findings suggest that NF2 alteration/22q loss is associated with recurrence in WHO grade 1 sphenoid wing meningiomas.

SUBMITTER: Sakai Y

PROVIDER: S-EPMC9265038 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. METHODS:850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. RESULTS:Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n?=?426, 50%), was associated with male sex (64.4% %, p?=?0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n?=?56) or TP53 mutations (n?=?25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p?=?0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases-with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n?=?22) or PBRM1 (n?=?16). A second subgroup contained AKT1 (n?=?26), PIK3CA (n?=?14) and SMO (n?=?7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. CONCLUSIONS:Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB APPROVAL STATUS:Reviewed and approved by Western IRB; Protocol No. 20152817.

Project description:BackgroundAtypical meningiomas exhibit a high tendency for tumor recurrence even after multimodal therapy. Information regarding recurrence patterns after additive radiotherapy is scarce but could improve radiotherapy planning and therapy decision. We conducted an analysis of recurrence patterns with regard to target volumes and dose coverage assessing target volume definition and postulated areas of tumor re-growth origin. Prognostic factors contributing to relapse were evaluated.MethodsThe clinical outcome of patients who had completed additive, somatostatin receptor (SSTR)-PET/CT-based fractionated intensity-modulated radiotherapy for atypical meningioma between 2007 and 2017 was analyzed. In case of tumor recurrence/progression, treatment planning was evaluated for coverage of the initial target volumes and the recurrent tumor tissue. We proposed a model evaluating the dose distribution in postulated areas of tumor re-growth origin. The median of proliferation marker MIB-1 was assessed as a prognostic factor for local progression and new distant tumor lesions.ResultsData from 31 patients who had received adjuvant (n = 11) or salvage radiotherapy (n = 20) were evaluated. Prescribed dose ranged from 54.0 to 60.0 Gy. Local control at five years was 67.9%. Analysis of treatment plans of the eight patients experiencing local failure proved sufficient extent of target volumes and coverage of the prescribed dose of at least 50.0 Gy as determined by mean dose, D98, D2, and equivalent uniform dose (EUD) of all initial target volumes, postulated growth-areas, and areas of recurrent tumor tissue. In all cases, local failure occurred in high-dose volumes. Tumors with a MIB-1 expression above the median (8%) showed a higher tendency for re-growth.ConclusionsThe model showed adequate target volume and relative dose distribution but absolute dose appears lower in recurrent tumors without reaching statistical significance. This might provide a rationale for dose escalation studies. Biological factors such as MIB-1 might aid patients' stratification for dose escalation.

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NF2 Alteration/22q Loss Is Associated with Recurrence in WHO Grade 1 Sphenoid Wing Meningiomas.

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