Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Reuß, David; Piro, Rosario M.; Jones, David; Simon, Matthias; Ketter, Ralf; Kool, Marcel; Becker, Albert J.; Sahm, Felix; Pusch, Stefan; Meyer, J.; Hagenlocher, Christian; Schweizer, Leonille; Capper, David; Kickingereder, Phillipp; Mucha, Jana; Koelsche, Christian; Jäger, Natalie; Santarius, Thomas; Tarpey, Patrick; Stephens, Philip J.; Futreal, P. Andrew; Wellenreuther, Ruth; Kraus, Jürgen; Lenartz, Doris; Herold‐Mende, Christel; Hartmann, Christian; Mawrin, Christian; Giese, Nathalia A.; Eils, Roland; Collins, V. Peter; König, Rainer; Wiestler, Otmar D.; Pfister, Stefan M.; Deimling, Andreas von

doi:10.1007/s00401-013-1093-x

Cited by 223 publications

(218 citation statements)

References 29 publications

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“…24,25 KLF4 mutations have been identified in colon cancer and meningiomas. 14,26,27 To examine the function of KLF4 in lung cancer, we analyzed KLF4 mutations in lung cancer patients from the The Cancer Genome Atlas (TCGA) adenocarcinoma database. In all, 9 out of 488 patients had KLF4 mutations.…”

Section: Resultsmentioning

confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. To identify novel factors that contribute to lung cancer pathogenesis, we analyzed a lung cancer database from The Cancer Genome Atlas and found that Krüppel-like Factor 4 (KLF4) expression is significantly lower in patients' lung cancer tissue than in normal lung tissue. In addition, we identified seven missense mutations in the KLF4 gene. KLF4 is a transcription factor that regulates cell proliferation and differentiation as well as the self-renewal of stem cells. To understand the role of KLF4 in the lung, we generated a tamoxifeninduced Klf4 knockout mouse model. We found that KLF4 inhibits lung cancer cell growth and that depletion of Klf4 altered the differentiation pattern in the developing lung. To understand how KLF4 functions during lung tumorigenesis, we generated the K-ras LSL-G12D/+ ;Klf4 fl/fl mouse model, and we used adenovirus-expressed Cre to induce K-ras activation and Klf4 depletion in the lung. Although Klf4 deletion alone or K-ras mutation alone can trigger lung tumor formation, Klf4 deletion combined with K-ras mutation significantly enhanced lung tumor formation. We also found that Klf4 deletion in conjunction with K-ras activation caused lung inflammation. To understand the mechanism whereby KLF4 is regulated during lung tumorigenesis, we analyzed KLF4 promoter methylation and the profiles of epigenetic factors. We found that Class I histone deacetylases (HDACs) are overexpressed in lung cancer and that HDAC inhibitors induced expression of KLF4 and inhibited proliferation of lung cancer cells, suggesting that KLF4 is probably repressed by histone acetylation and that HDACs are valuable drug targets for lung cancer treatment.

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Section: Resultsmentioning

confidence: 99%

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Chen

Zhang

et al. 2015

Cell Death Differ

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“…In terms of histological findings, we also confirmed the genotype-oriented histological pattern: all fibrous meningiomas were classified into NF2 type, and secretory component was associated with mutation in TRAF7 and KLF4; these trends were similar to previous reports. 9,21,22 In addition, tumor size of NF2 type was larger than that of TRAKLS types, probably because of high proliferative ability. In fact, NF2 type meningioma showed higher Ki-67 LI compared with TRAKLS type, and this result is compatible with previous studies 14 has expanded the application of targeted amplicon sequencing.…”

Section: Discussionmentioning

confidence: 99%

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

et al. 2016

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Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgenefixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.

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“…74 The KLF4 mutation has not been observed in any other nonsecretory meningiomas, CNS tumors, or systemic malignancies. TRAF7 mutations overlap with KLF4 mutations but are found in a larger spectrum of meningioma subtypes, 22 including 97% of secretory meningiomas and 8% of nonsecretory meningiomas.…”

Section: Genetic Hallmarks Of Meningioma Subtypesmentioning

confidence: 99%

“…22 A majority of meningiomas with TRAF7 mutations also harbor mutations in AKT1 or KLF4 mutations, but not both. 22,74 However, TRAF7 mutations occur in a mostly mutually exclusive fashion with SMO mutations, NF2 mutations, and chromosome 22 loss. 22 The mechanism and downstream effectors of this mutation remain to be discovered.…”

Section: Somatic Mutations Revealed By Next-generation Sequencing Appmentioning

confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

104

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M eningioMas are the most common primary intracranial neoplasms in adults, accounting for 35.8% of all primary CNS tumors and more than 53% of all benign CNS tumors diagnosed in the US. 65 Autopsy and imaging studies suggest an even higher prevalence, affecting almost 3% of women.98 These lesions are believed to arise from progenitor cells that give rise to both the arachnoid cap cells of the arachnoid layer and fibroblasts that reside in the inner dura mater. 18,45The vast majority of meningiomas are indolent.36 A small percentage, however, display malignant behavior characterized by invasive growth patterns and/or markedly higher recurrence rates. Notably, even meningiomas that lack histological features of malignancy recur at significant rates. Multimodality therapy including surgery and radiation is often used in the management of these subsets of meningioma, but other therapeutic modalities have failed to improve control rates. Aggressive meningiomas and the meningiomatosis that occur in hereditary syndromes remain difficult clinical problems. Although most meningiomas are "benign," there is substantial morbidity associated with recurrence, and clinical management remains challenging for clinicians worldwide.Unbiased genome-and exome-wide sequencing approaches have implicated a central core of gene mutations that are associated with a substantial percentage of these tumors. This information may highlight therapeutic targets and enhance biological classification of meningioma. 12,22 Just as an improved understanding of genomic alterations has changed the way we classify and treat cancers including chronic myelogenous leukemia, melanoma, and lung cancer, similar interrogation of the meningioma genome has revealed potential novel treatment pathways for patients harboring these tumors. Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased nextgeneration sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

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Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Cited by 223 publications

References 29 publications

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer

Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system

Genomic landscape of intracranial meningiomas

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