Mutations In TRAF7 Research Articles

Genetic landscape of meningioma.

Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55% of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3% of cases, respectively. Altogether, 80% of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas.

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes, including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO, we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features.

Abstract LB-331: Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations

Abstract Malignant pleural mesothelioma (MPM) is an aggressive cancer arising from the mesothelial cells of the pleura. About 80% of mesothelioma cases are linked to asbestos exposure, while the remainder may be related to prior chest radiation, genetic predisposition or spontaneous occurrence. We analyzed transcriptomes (n = 211), whole exomes (n = 99), and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Four distinct molecular subtypes, sarcomatoid (S), epithelioid (E), biphasic-E, and biphasic-S were identified using RNA-seq data. Using exome analysis we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1, and DDX51 to be significantly mutated MPM genes. We identified recurrent mutations in several genes including splice complex factor SF3B1 (∼2% [4/216]) and TRAF7 (∼2% [5/216]). SF3B1 mutant samples showed a distinct splicing profile compared to wild-type tumors. Mutations in TRAF7 occurred primarily in the WD40 domain and except in one case were mutually exclusive with NF2 mutations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. We analyzed the tumors for infiltrating immune cells and found that M2 macrophage to T-cell ratio was predictive of reduced overall survival. Further we found sarcomatoid subtype had a significantly higher level of PD-L1 expression suggesting that this group might be prioritized for checkpoint inhibitor therapy. Integrated analysis of alterations identified changes in Hippo, mTOR, Histone methylation, RNA helicase and p53 signaling pathways in MPMs. Overall our study significantly expands on the previous genomic studies and provides a comprehensive genomics profile of mesothelioma and identifies several previously unknown alterations and biological pathways that are potential targets for drug discovery and treatment. Incorporating genomic analysis for detection of actionable alterations as part of MPM patient care will help in developing rational individualized therapy. Citation Format: Somasekar Seshagiri, Eric Stawiski, Leonard Goldstein, Steffen Durinck, Zora Modrusan, Florian Gnad, Thong T. Nguyen, Bijay Jaiswal, Assunta De Rienzo, William Richards, Raphael Bueno. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-331.

Meningioma Genomics: Diagnostic, Prognostic, and Therapeutic Applications.

There has been a recent revolution in our understanding of the genetic factors that drive meningioma, punctuating an equilibrium that has existed since Cushing’s germinal studies nearly a century ago. A growing appreciation that meningiomas share similar biologic features with other malignancies has allowed extrapolation of management strategies and lessons from intra-axial central nervous system neoplasms and systemic cancers to meningiomas. These features include a natural proclivity for invasion, frequent intratumoral heterogeneity, and correlation between biologic profile and clinical behavior. Next-generation sequencing has characterized recurrent somatic mutations in NF2, TRAF7, KLF4, AKT1, SMO, and PIK3CA, which are collectively present in ~80% of sporadic meningiomas. Genomic features of meningioma further associate with tumor location, histologic subtype, and possibly clinical behavior. Such genomic decryption, along with advances in targeted pharmacotherapy, provides a maturing integrated view of meningiomas. We review recent advances in meningioma genomics and probe their potential applications in diagnostic, therapeutic, and prognostic frontiers.

Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.

We analyzed transcriptomes (n = 211), whole exomes (n = 99) and targeted exomes (n = 103) from 216 malignant pleural mesothelioma (MPM) tumors. Using RNA-seq data, we identified four distinct molecular subtypes: sarcomatoid, epithelioid, biphasic-epithelioid (biphasic-E) and biphasic-sarcomatoid (biphasic-S). Through exome analysis, we found BAP1, NF2, TP53, SETD2, DDX3X, ULK2, RYR2, CFAP45, SETDB1 and DDX51 to be significantly mutated (q-score ≥ 0.8) in MPMs. We identified recurrent mutations in several genes, including SF3B1 (∼2%; 4/216) and TRAF7 (∼2%; 5/216). SF3B1-mutant samples showed a splicing profile distinct from that of wild-type tumors. TRAF7 alterations occurred primarily in the WD40 domain and were, except in one case, mutually exclusive with NF2 alterations. We found recurrent gene fusions and splice alterations to be frequent mechanisms for inactivation of NF2, BAP1 and SETD2. Through integrated analyses, we identified alterations in Hippo, mTOR, histone methylation, RNA helicase and p53 signaling pathways in MPMs.

Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma.

Meningiomas are the most common primary intracranial tumor in adults. Identification of SMO and AKT1 mutations in meningiomas has raised the possibility of targeted therapies for some patients. The frequency of such mutations in clinical cohorts and the presence of other actionable mutations in meningiomas are important to define. We used high-resolution array-comparative genomic hybridization to prospectively characterize copy-number changes in 150 meningiomas and then characterized these samples for mutations in AKT1, KLF4, NF2, PIK3CA, SMO, and TRAF7. Similar to prior reports, we identified AKT1 and SMO mutations in a subset of non-NF2-mutant meningiomas (ie, ∼9% and ∼6%, respectively). Notably, we detected oncogenic mutations in PIK3CA in ∼7% of non-NF2-mutant meningiomas. AKT1, SMO, and PIK3CA mutations were mutually exclusive. AKT1, KLF4, and PIK3CA mutations often co-occurred with mutations in TRAF7. PIK3CA-mutant meningiomas showed limited chromosomal instability and were enriched in the skull base. This work identifies PI3K signaling as an important target for precision medicine trials in meningioma patients.

MNGO-21GENOTYPING OF MENINGIOMA BY TARGETED AMPLICON SEQUENCING USING MiSeq

BACKGROUND: Meningiomas are the most common primary brain tumors, accounting for about 27% of all intracranial tumors. Loss of Neurofibromin 2 (NF2) is found in about half of sporadic meningiomas, and recently, mutations in TRAF7, KLF4, AKT1, and SMO are reported in non-NF2 meningioma. To establish practical genotyping methods, we performed targeted amplicon sequencing with 45 meningioma specimens and evaluated the association with clinicopathological features. METHODS: Frozen samples of 45 meningiomas were fixed with PAXgene Tissue System (QIAGEN) and embedded in paraffin (PFPE). Amplicon sequencing panel targeted NF2, TRAF7, KLF4, AKT1 and SMO were designed by GeneRead Mix-n-Match panel and Custom panel (QIAGEN). Genomic DNA was extracted from PFPE tissues and libraries were prepared using GeneRead DNAseq Targeted Panels V2 (QIAGEN). The libraries were sequenced by the MiSeq (Illumina). The raw read data obtained from amplicon sequencing were processed by GeneRead Panel Variant Calling service for analysis of mutations and copy number alterations (CNA). RESULTS: Thirty three cases (73%) harbored NF2 loss, in which 20 cases (61%) simultaneously carried NF2 mutation. Mutations in TRAF7, KLF4, AKT1, and SMO were observed in 6 (13 %), 4 (9 %), 2 (4 %) and 0 (0%) cases, respectively. Altogether, 40 of 45 case (89 %) carried at least one or more gene alteration including mutations in 5 genes listed above and NF2 loss. Result of genotyping was correlated with histological subtypes as follows. All of nine fibrous meningiomas carried NF2 loss, while all of 4 meningiomas with secretory component carried both TRAF7 and KLF4 mutations. A case of chordoid meningioma harbored only AKT1-E17K mutation. CONCLUSIONS: Here we established the clinical sequence system for meningioma by targeted amplicon sequencing with desktop sequencer in which we demonstrated favorable results for CNAs as well as mutations.

Biology and clinical management challenges in meningioma.

Meningiomas are the most frequently occurring intracranial tumors. They are characterized by a broad spectrum of histopathologic appearance. Molecular alterations driving meningioma development, which affect the NF2 gene, are found in roughly 50% of patients. Rare genetic events in benign meningiomas are mutations in TRAF7, KLF4, AKT1, and SMO; all of these mutations are exclusive of NF2 alterations. Progression to a clinically aggressive meningioma is linked to inactivation of CDKN2A/B genes, and a plethora of signaling molecules have been described as activated in meningiomas, which supports the concept of successful clinical use of specific inhibitors. Established treatments include surgical resection with or without radiotherapy delivered in a single fraction, a few large fractions (radiosurgery), or multiple fractions (fractionated radiotherapy). For recurrent and aggressive tumors, inhibitors of the vascular endothelial growth factor (VEGF) pathway, such as vatalinib, bevacizumab, and sunitinib, showed signs of activity in small, uncontrolled studies, and prospective clinical studies will test the efficacy of the tetrahydroisoquinoline trabectedin and of SMO and AKT1 inhibitors.

16IN - Meningioma: what Can we Learn from the Biology for Precision Medicine?

ABSTRACT Meningiomas differ considerably by their histological appearance, location, biological behavior, recurrence rate, and overall survival. The most frequent alteration found in sporadic meningioma corresponds to biallelic NF2 inactivation. Besides the central role of NF2, other alternative genetic alterations have been recently identified in meningioma initiation. The AKT1E17K mutation was found in 12%, predominantly in benign skull base meningiomas, occurring frequently together with mutations in the TRAF7 gene. TRAF7 mutations are exclusively of NF2 mutations and occur in about 24% of meningiomas. In addition, meningiomas with TRAF7 mutations are almost always characterized by recurrent mutation in the KLF4 gene (co-regulator of the bradykinin B2 receptor). Another non-NF2-associated mutation of meningiomas affects the SMO (Smoothened) gene which is a member of the hedgehog pathway. SMO mutations occur in 5% of grade I meningiomas and are restricted to the midline skull base. Meningioma progression and recurrence are linked to chromosome instability, CDKN2AB genes on chromosome 9p being suspected to be important. Mouse models that reproduce human meningioma tumorigenesis have been developed. Two conditional Nf2 knockout models have shown that Nf2 inactivation in leptomeningeal cells of mice is sufficient to induce meningiomas. Additional deletion of Cdkn2ab, together with Nf2 inactivation, results in increased meningioma frequency, as well as development of grade II or grade III meningiomas. All relevant growth factor receptors/kinases have been described to be expressed in meningiomas, including epidermal growth factor receptor (EGFR), platelet-derived growth factor beta receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and insulin-like growth factor receptor (IGFR). A new mouse model surexpressing PDGF-beta has been recently developed showing an increase in frequency and malignancy in association with Nf2 and Cdkn2ab inactivation. In conclusion, increasing knowledge on the molecular mechanisms of meningioma initiation and development provides target that could be relevant to develop new therapeutic approaches, particularly in surgery and radiotherapy-refractory meningiomas. Disclosure: All authors have declared no conflicts of interest.

Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations

Meningiomas are among the most frequent intracranial tumors. The secretory variant of meningioma is characterized by glandular differentiation, formation of intracellular lumina and pseudopsammoma bodies, expression of a distinct pattern of cytokeratins and clinically by pronounced perifocal brain edema. Here we describe whole-exome sequencing analysis of DNA from 16 secretory meningiomas and corresponding constitutional tissues. All secretory meningiomas invariably harbored a mutation in both KLF4 and TRAF7. Validation in an independent cohort of 14 secretory meningiomas by Sanger sequencing or derived cleaved amplified polymorphic sequence (dCAPS) assay detected the same pattern, with KLF4 mutations observed in a total of 30/30 and TRAF7 mutations in 29/30 of these tumors. All KLF4 mutations were identical, affected codon 409 and resulted in a lysine to glutamine exchange (K409Q). KLF4 mutations were not found in 89 non-secretory meningiomas, 267 other intracranial tumors including gliomas, glioneuronal tumors, pituitary adenomas and metastases, 59 peripheral nerve sheath tumors and 52 pancreatic tumors. TRAF7 mutations were restricted to the WD40 domains. While KLF4 mutations were exclusively seen in secretory meningiomas, TRAF7 mutations were also observed in 7/89 (8 %) of non-secretory meningiomas. KLF4 and TRAF7 mutations were mutually exclusive with NF2 mutations. In conclusion, our findings suggest an essential contribution of combined KLF4 K409Q and TRAF7 mutations in the genesis of secretory meningioma and demonstrate a role for TRAF7 alterations in other non-NF2 meningiomas.