Intratumoral heterogeneity and <i>TERT</i> promoter mutations in progressive/higher-grade meningiomas

Juratli, Tareq A.; Thiede, Christian; Koerner, Mara V.A.; Tummala, Shilpa S.; Daubner, Dirk; Shankar, Ganesh M.; Williams, Erik A.; Martinez‐Lage, Maria; Soucek, Silke; Robel, Katja; Penson, Tristan; Krause, Mechthild; Appold, Steffen; Meinhardt, Matthias; Pinzer, Thomas; Miller, Julie J.; Krex, Dietmar; Ely, Heather A.; Silverman, Ian M.; Christiansen, Jason; Schackert, Gabriele; Wakimoto, Hiroaki; Kirsch, Matthias; Brastianos, Priscilla K.; Cahill, Daniel P.

doi:10.18632/oncotarget.22650

Cited by 100 publications

(87 citation statements)

References 24 publications

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“…Finally, while novel fusions were recently discovered in a subset of meningiomas, 26,27,33 we did not detect any clinically actionable gene fusions in the meningiomas in our study. This may be explained by the fact that the majority of the cases in our cohort have a low-grade histology, whereas gene fusions, such as those involving TERT (telomerase reverse transcriptase), have been described in high-grade meningiomas.…”

Section: Discussioncontrasting

confidence: 77%

“…This may be explained by the fact that the majority of the cases in our cohort have a low-grade histology, whereas gene fusions, such as those involving TERT (telomerase reverse transcriptase), have been described in high-grade meningiomas. 27,33 Furthermore, while NF2 gene rearrangements have been reported in patients who received cranial irradiation in childhood, this group of patients was excluded in our study.…”

Section: Discussionmentioning

confidence: 99%

“…Fusion oncogenes have been described in several human cancers including meningiomas 26,27 and have been successfully targeted in several tumor types. 28 To assess whether clinically targetable gene fusions were present in posterior fossa meningiomas, we performed targeted RNA fusion gene analysis in all samples using Archer FusionPlex and did not detect any relevant RNA fusion transcripts (►Table 1).…”

Section: Gene Rearrangements Are Not Common In Posterior Fossa Meningmentioning

confidence: 99%

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Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas

et al. 2019

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Objective Posterior fossa meningiomas are surgically challenging tumors that are associated with high morbidity and mortality. We sought to investigate the anatomical distribution of clinically actionable mutations in posterior fossa meningioma to facilitate identifying patients amenable for systemic targeted therapy trials. Methods Targeted sequencing of clinically targetable AKT1, SMO, and PIK3CA mutations was performed in 61 posterior fossa meningioma using Illumina NextSeq 500 to a target depth of >500 × . Samples were further interrogated for 53 cancer-relevant RNA fusions by the Archer FusionPlex panel to detect gene rearrangements. Results AKT1 (E17K) mutations were detected in five cases (8.2%), four in the foramen magnum and one in the cerebellopontine angle. In contrast, none of the posterior fossa tumors harbored an SMO (L412F) or a PIK3CA (E545K) mutation. Notably, the majority of foramen magnum meningiomas (4/7, 57%) harbored an AKT1 mutation. In addition, common clinically targetable gene fusions were not detected in any of the cases. Conclusion A large subset of foramen magnum meningiomas harbor AKT1 E17K mutations and are therefore potentially amenable to targeted medical therapy. Genotyping of foramen magnum meningiomas may enable more therapeutic alternatives and guide their treatment decision process.

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Section: Discussioncontrasting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Section: Gene Rearrangements Are Not Common In Posterior Fossa Meningmentioning

confidence: 99%

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Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas

et al. 2019

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“…Associations between epigenetic modification and aggressiveness in meningioma have so far mostly been assessed on the level of DNA methylation. Thereby, DNA methylation analysis has evolved as promising candidate to add a molecular layer to upcoming WHO classifications, along with risk-related genetic aberrations like TERT promoter or BAP1 mutations [11,14,23,29,32].…”

Section: Discussionmentioning

confidence: 99%

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence

et al. 2018

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Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II.

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“…Recently, the association of telomerase reverse transcriptase (TERT) promoter mutations with malignant progression in meningioma has been reported . Interestingly, spatial intratumoral heterogeneity of TERT promoter mutations was observed . Amid calls for the need to standardize the surgical sampling technique, evaluation of the proliferative potential of residual or affected tissues is obviously necessary for a more accurate estimation of recurrence, especially in situations where the possibility of non‐benign meningiomas is suspected.…”

Section: Discussionmentioning

confidence: 99%

Intraoperative quantification of meningioma cell proliferation potential using rapid flow cytometry reveals intratumoral heterogeneity

et al. 2019

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Background Standard sampling methods to evaluate the proliferative ability of meningioma have not been established. Methods This prospective study was conducted to evaluate the effectiveness of intraoperative rapid flow cytometry (iFC) using raw samples for the quantitative assessment of proliferative ability in meningioma cells and to investigate intratumoral heterogeneity. Proliferation index (PI) was defined as the ratio of aneuploid cells with an abnormal number of chromosomes to the total cells. Results From 50 patients, 118 specimens were analyzed. There was a statistically significant correlation between the postoperative MIB‐1 labeling index (LI) and PI (R = 0.59, P < 0.0001). A higher PI was correlated with a higher annual growth rate (AGR, cm3/y) (R = 0.50, P = 0.0002, 26 patients). AGR showed a correlation with the intratumoral distribution of PI. PI was the highest at the center or the peripheral section of the tumor in tumors with high AGR, whereas it was highest at the dural attachment in tumors with low AGR (P = 0.039, n = 20). Pial feeders were more frequently observed when PI was high in the center or in the peripheral section (P = 0.006, n = 37). Conclusions Rapid iFC may thus become a substitute for MIB‐1 LI. Intratumoral heterogeneity of cellular proliferative potential exists in meningiomas and is related to tumor biological characteristics such as AGR and development of pial feeders. This observation underscores the importance of standardization in the sampling method to accurately estimate the risk of meningioma recurrence.

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Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas

Cited by 100 publications

References 24 publications

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas

Genomic Analysis of Posterior Fossa Meningioma Demonstrates Frequent AKT1 E17K Mutations in Foramen Magnum Meningiomas

Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence

Intraoperative quantification of meningioma cell proliferation potential using rapid flow cytometry reveals intratumoral heterogeneity

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