Smarcb1-Mutant Intracranial Meningiomas: A Distinct Subtype Of Nf2-Mutant Tumors

Meningiomas are the most common central nervous system primary tumors. Mutations in the tumor suppressor gene Neurofibromin 2 (NF2), located on chromosome 22 (Chr22), are present in 40-50% of sporadic meningiomas. In a subset of non-NF2-mutant meningiomas, recent studies have identified tumorigenesis driver mutations in the genes TRAF7, AKT1, KLF4, and SMO. However, the genetic basis for the marked clinical and histological heterogeneity that exists among NF2-mutant/Chr22-loss meningiomas remains to be established. In this study, we utilized next-generation sequencing techniques to identify and screen a large cohort of NF2-mutant/Chr22-loss meningiomas for concurrent co-driver mutations in novel genes that may contribute to the observed clinical and histological heterogeneity of these tumors. We identified 25 NF2-mutant/Chr22-loss meningiomas that harbored concurrent somatic mutations in the SMARCB1 gene. SMARCB1 codes for a component of the SWI/SNF complex and is involved in epigenetic modification via nucleosome modulation and chromatin remodeling. SMARCB1 is also known to interact with GLI1, an important effector of the Hedgehog pathway, and EZH2, a member of the Polycomb-group proteins that is capable of epigenetically silencing gene expression via histone methylation. SMARCB1 somatic mutations have previously been associated with the highly aggressive malignant rhabdoid tumors and germline variants have previously been identified as the driver mutation responsible for familial schwannomatosis. Notably, a subset of patients with familial schwannomatosis develop multiple meningiomas as part of their disease course. We performed RNA expression analysis to determine gene expression differences in SMARCB1-mutant meningiomas versus non-SMARCB1-mutant meningiomas. Unsupervised hierarchical clustering demonstrated that the expression profiles of SMARCB1-mutant meningiomas cluster similarly to other NF2-mutant/Chr22 loss meningiomas. However, within this superfamily, SMARCB1-mutant meningiomas form distinct subgroups. This differential clustering is due, at least in part, to increased GLI1 and EZH2 expression suggesting that SMARCB1-mutant tumors represent a distinct genetic subtype of NF2-mutant meningiomas. Genomic-clinical correlates for SMARCB1-mutant tumors showed no significant differences in this cohort in age at time of surgery (median = 64 years), gender predilection (80% female), or low-grade histologic subtype when compared to the natural history literature. However, the SMARCB1-mutant meningiomas were predominantly midline tumors (71%) with increased propensity to being high- grade lesions (36%), despite remarkable chromosomal stability. These clinical findings strongly paralleled our genetic data suggesting that increased expression of GLI and EZH2 may, respectively, contribute to the midline tumor location and serve as a substitute for widespread chromosomal instability in high-grade lesions. These results demonstrate that SMARCB1-mutant meningiomas represent a genetically and phenotypically distinct sub-group of NF2-mutant meningiomas and partially contribute to the observed clinical heterogeneity of convexity lesions. This study also suggests potential targets for therapeutic interventions that warrant future investigation

Демографический потенциал Республики Беларусь

Материалы III Междунар. науч. конф. студентов, аспирантов и молодых ученых, Гомель, 20 мая 2010 г

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 SMO4 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

Cerebral cavernous malformations: Review of the genetic and protein-protein interactions resulting in disease pathogenesis

Mutations in the genes KRIT1, CCM2, and PDCD10 are known to result in the formation of cerebral cavernous malformations (CCMs). CCMs are intracranial lesions comprised of aberrantly enlarged cavernous endothelial channels that can result in cerebral hemorrhage, seizures, and neurologic deficits. Although these genes have been known to be associated with CCMs since the 1990s, numerous discoveries have been made that better elucidate how they and their subsequent protein products are involved in CCM pathogenesis. Since our last review of the molecular genetics of CCM pathogenesis in 2012, breakthroughs include a more thorough understanding of the protein structures of the gene products, involvement with integrin proteins and MEKK3 signaling pathways, the importance of CCM2-PDCD10 interactions, and others. In this review, we highlight the advances that further our understanding of the gene to protein to disease relationships of CCMs

The middle communicating artery: A novel fourth-generation bypass for revascularizing trapped middle cerebral artery bifurcation aneurysms in 2 cases

The anterior and posterior communicating arteries are natural connections between arteries that enable different adjacent circulations to redistribute blood flow instantly in response to changing supply and demand. An analogous communication does not exist in the middle cerebral circulation. A middle communicating artery (MCoA) can be created microsurgically between separate middle cerebral artery (MCA) trunks, enabling flow to redistribute in response to changing supply and demand. The MCoA would draw blood flow from an adjacent circulation such as the external carotid circulation. The MCoA requires the application of fourth-generation techniques to reconstruct bi- and trifurcations after occluding complex MCA trunk aneurysms. In this report, the authors describe two recent cases of complex MCA bi- and trifurcation aneurysms in which the occluded efferent trunks were revascularized by creating an MCoA. The first MCoA was created with a “double-barrel” superficial temporal artery-M2 segment bypass and end-to-end reimplantation of the middle and inferior MCA trunks. The second MCoA was created with an external carotid artery-radial artery graft-M2 segment interpositional bypass and end-to-side reimplantation of the inferior trunk onto the superior trunk. Both aneurysms were occluded, and both patients experienced good outcomes. This report introduces the concept of the MCoA and demonstrates two variations. Angioarchitectural and technical elements include the donation of flow from an adjacent circulation, a communicating bypass, the application of fourth-generation bypass techniques, and a minimized ischemia time. The MCoA construct is ideally suited for rebuilding bi- and trifurcated anatomy after trapping or distally occluding complex MCA aneurysms

Superficial Femoral Artery Interposition Graft for Repair of a Ruptured Mycotic Common Carotid Artery Pseudoaneurysm: Case Report and Review of the Literature.

BACKGROUND: Indications for reconstruction of the common carotid artery (CCA) include trauma, iatrogenic injury, neoplastic growth (such as invasive neck carcinomas), postoperative infection, and cervical carotid aneurysm. Although various techniques and conduits have been described, the clinical scenario may preclude the use of the most commonly used grafts. We describe a case using a superficial femoral artery (SFA) interposition graft to repair the CCA and review the available literature, highlighting the feasibility of this technique for carotid artery reconstruction. CASE DESCRIPTION: A patient aged 51 years presented with a ruptured mycotic CCA pseudoaneurysm that developed in the setting of a pharyngeal-carotid fistula. Because of the presence of a pharyngeal-carotid fistula and active infection within the vessel wall, endovascular treatment of the pseudoaneurysm was not feasible, and open surgical correction was required to repair the fistulous connection. Furthermore, owing to the extensive soft tissue infection, the use of a synthetic or venous autograft conduit for repair of the artery was contraindicated. Therefore, we harvested a segment of the SFA and used it as an interposition graft to reconstruct the diseased CCA, achieving an excellent anatomic and clinical result. CONCLUSIONS: This case highlights the feasibility of using an SFA interposition graft for short-segment CCA reconstruction, which can provide significant utility in the setting of a hostile operative field due to prior infection or radiation

The middle communicating artery: a novel fourth-generation bypass for revascularizing trapped middle cerebral artery bifurcation aneurysms in 2 cases

The anterior and posterior communicating arteries are natural connections between arteries that enable different adjacent circulations to redistribute blood flow instantly in response to changing supply and demand. An analogous communication does not exist in the middle cerebral circulation. A middle communicating artery (MCoA) can be created microsurgically between separate middle cerebral artery (MCA) trunks, enabling flow to redistribute in response to changing supply and demand. The MCoA would draw blood flow from an adjacent circulation such as the external carotid circulation. The MCoA requires the application of fourth-generation techniques to reconstruct bi- and trifurcations after occluding complex MCA trunk aneurysms. In this report, the authors describe two recent cases of complex MCA bi- and trifurcation aneurysms in which the occluded efferent trunks were revascularized by creating an MCoA. The first MCoA was created with a “double-barrel” superficial temporal artery-M2 segment bypass and end-to-end reimplantation of the middle and inferior MCA trunks. The second MCoA was created with an external carotid artery-radial artery graft-M2 segment interpositional bypass and end-to-side reimplantation of the inferior trunk onto the superior trunk. Both aneurysms were occluded, and both patients experienced good outcomes. This report introduces the concept of the MCoA and demonstrates two variations. Angioarchitectural and technical elements include the donation of flow from an adjacent circulation, a communicating bypass, the application of fourth-generation bypass techniques, and a minimized ischemia time. The MCoA construct is ideally suited for rebuilding bi- and trifurcated anatomy after trapping or distally occluding complex MCA aneurysms