DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome

Juratli, Tareq A.; McCabe, Devin; Nayyar, Naema; Williams, Erik A.; Silverman, Ian M.; Tummala, Shilpa S.; Fink, Alex; Baig, Aymen; Martinez‐Lage, Maria; Selig, Martin K.; Bihun, Ivanna V.; Shankar, Ganesh M.; Penson, Tristan; Lastrapes, Matthew; Daubner, Dirk; Meinhardt, Matthias; Hennig, Silke; Kaplan, Alexander; Shimizu, Fujio; Kuter, Benjamin M.; Bertalan, Mia; Miller, Julie J.; Batten, Julie M.; Ely, Heather A.; Christiansen, Jason; Baretton, Gustavo; Stemmer‐Rachamimov, Anat; Santagata, Sandro; Rivera, Miguel N.; Barker, Fred G.; Schackert, Gabriele; Wakimoto, Hiroaki; Iafrate, A. John; Carter, Scott L.; Cahill, Daniel P.; Brastianos, Priscilla K.

doi:10.1007/s00401-018-1899-7

Cited by 67 publications

(80 citation statements)

References 60 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: 75%

“…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%

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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: 75%

Section: Discussionmentioning

confidence: 99%

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

et al. 2019

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“…Juratli et al . showed that TERT promoter mutations and RETREG1‐TERT rearrangement were present in recurrent meningioma samples, and TERT mutation predicted unfavourable clinical outcomes . Peyre et al .…”

Section: Discussionmentioning

confidence: 99%

Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression

Kim

Park

Ryu

et al. 2019

Neuropathology Appl Neurobio

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2020) Neuropathology and Applied Neurobiology 46, 125-141 Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression Aims: Aggressive meningioma remains incurable with neither chemo-nor targeted therapies proven effective, largely due to unidentified genetic alterations and/or aberrant oncogenic pathways driving the disease progression. In this study, we examined the expression and function of Forkhead box M1 (FOXM1) transcription factor during meningioma progression. Methods: Human meningioma samples (n = 101) were collected, followed by Western blotting, quantitative PCR, immunohistochemical and progression-free survival (PFS) analyses. For in vitro assays, FOXM1 was overexpressed or knocked-down in benign (SF4433 and SF4068) or malignant (SF3061 and IOMM-Lee) human meningioma cell lines respectively. For in vivo studies, siomycin A (a FOXM1 inhibitor)-pretreated or control IOMM-Lee cells were implanted subcutaneously in nude mice. Results: FOXM1 expression was increased in higher grades of meningioma and correlated with the mitotic index in the tumour tissue. Moreover, FOXM1 was increased in recurrent meningioma compared with the matched primary lesions. The patients who had higher FOXM1 expression had shorter PFS. In the subsequent in vitro assays, knockdown of FOXM1 in malignant meningioma cell lines resulted in decreased tumour cell proliferation, angiogenesis and invasion, potentially via regulation of b-catenin, cyclin D1, p21, interleukin-8, vascular endothelial growth factor-A, PLAU, and epithelial-to-mesenchymal transition-related genes, whereas overexpression of FOXM1 in benign meningioma cell lines had the opposite effects. Last, suppression of FOXM1 using a pharmacological inhibitor, siomycin A, decreased tumour growth in an in vivo mouse model. Conclusions: Our data demonstrate that FOXM1 is a key transcription factor regulating oncogenic signalling pathways in meningioma progression, and a promising therapeutic target for aggressive meningioma.

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“…However, a detailed analysis was not performed in these earlier reports. Recently, using highthroughput sequencing, this genomic event has been identified to activate telomerase in many cancer types, including neuroblastoma, glioblastoma, meningiomas, malignant melanoma and pheochromocytomas, chromophobe renal cell carcinoma (ChRCC), HCC, and among others [71][72][73][74][75][76][77][78] (Fig. 3b).…”

Section: The Tert Gene Rearrangementsmentioning

confidence: 99%

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

2019

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Long-lived species Homo sapiens have evolved robust protection mechanisms against cancer by repressing telomerase and maintaining short telomeres, thereby delaying the onset of the majority of cancer types until post-reproductive age. Indeed, telomerase is silent in most differentiated human cells, predominantly due to the transcriptional repression of its catalytic component telomerase reverse transcriptase (TERT) gene. The lack of telomerase/TERT expression leads to progressive telomere erosion in dividing human cells, whereas critically shortened telomere length induces a permanent growth arrest stage named replicative senescence. TERT/telomerase activation has been experimentally shown to be essential to cellular immortalization and malignant transformation by stabilizing telomere length and erasing the senescence barrier. Consistently, TERT expression/telomerase activity is detectable in up to 90% of human primary cancers. Compelling evidence has also accumulated that TERT contributes to cancer development and progression via multiple activities beyond its canonical telomere-lengthening function. Given these key roles of telomerase and TERT in oncogenesis, great efforts have been made to decipher mechanisms underlying telomerase activation and TERT induction. In the last two decades since the TERT gene and promoter were cloned, the derepression of the TERT gene has been shown to be achieved typically at a transcriptional level through dysregulation of oncogenic factors or signaling, post-transcriptional/translational regulation and genomic amplification. However, advances in high-throughput next-generation sequencing technologies have prompted a revolution in cancer genomics, which leads to the recent discovery that genomic alterations take center stage in activating the TERT gene. In this review article, we summarize critical mechanisms activating TERT transcription, with special emphases on the contribution of TERT promoter mutations and structural alterations at the TERT locus, and briefly discuss the underlying implications of these genomic events-driven TERT hyperactivity in cancer initiation/progression and potential clinical applications as well.

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DMD genomic deletions characterize a subset of progressive/higher-grade meningiomas with poor outcome

Cited by 67 publications

References 60 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

Forkhead box M1 (FOXM1) transcription factor is a key oncogenic driver of aggressive human meningioma progression

Mechanisms underlying the activation of TERT transcription and telomerase activity in human cancer: old actors and new players

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