Glioblastoma-derived extracellular vesicles induce tumor-supportive phenotypes in monocytic cells
; ; et al
in International Journal of Cancer = Journal International du Cancer (in press)Detailed reference viewed: 14 (2 ULg)
High Resolution postontrast time of flight MR angiography of intracranial perforators at 7.0 Tesla
; ; et al
in American Journal of Neuroradiology (in press)Detailed reference viewed: 9 (0 ULg)
Connexin 30 expression inhibits growth of human malignant gliomas but protects them against radiation therapy.
Artesi, Maria ; ; et al
in Neuro-oncology (2014)
BACKGROUND: Glioblastomas remain ominous tumors that almost invariably escape treatment. Connexins are a family of transmembrane, gap junction-forming proteins, some members of which were reported to act ... [more ▼]
BACKGROUND: Glioblastomas remain ominous tumors that almost invariably escape treatment. Connexins are a family of transmembrane, gap junction-forming proteins, some members of which were reported to act as tumor suppressors and to modulate cellular metabolism in response to cytotoxic stress. METHODS: We analyzed the copy number and expression of the connexin (Cx)30 gene gap junction beta-6 (GJB6), as well as of its protein immunoreactivity in several public and proprietary repositories of glioblastomas, and their influence on patient survival. We evaluated the effect of the expression of this gap junction protein on the growth, DNA repair and energy metabolism, and treatment resistance of these tumors. RESULTS: The GJB6 gene was deleted in 25.8% of 751 analyzed tumors and mutated in 15.8% of 158 tumors. Cx30 immunoreactivity was absent in 28.9% of 145 tumors. Restoration of Cx30 expression in human glioblastoma cells reduced their growth in vitro and as xenografts in the striatum of immunodeficient mice. Cx30 immunoreactivity was, however, found to adversely affect survival in 2 independent retrospective cohorts of glioblastoma patients. Cx30 was found in clonogenic assays to protect glioblastoma cells against radiation-induced mortality and to decrease radiation-induced DNA damage. This radioprotection correlated with a heat shock protein 90-dependent mitochondrial translocation of Cx30 following radiation and an improved ATP production following this genotoxic stress. CONCLUSION: These results underline the complex relationship between potential tumor suppressors and treatment resistance in glioblastomas and single out GJB6/Cx30 as a potential biomarker and target for therapeutic intervention in these tumors. [less ▲]Detailed reference viewed: 18 (9 ULg)
Changing incidence and improved survival of gliomas.
; ; et al
in European journal of cancer (Oxford, England : 1990) (2014), 50(13), 2309-18
BACKGROUND: Tumours of the central nervous system (CNS) represent a relatively rare but serious health burden. This study provides insight into the incidence and survival patterns of gliomas in the ... [more ▼]
BACKGROUND: Tumours of the central nervous system (CNS) represent a relatively rare but serious health burden. This study provides insight into the incidence and survival patterns of gliomas in the Netherlands diagnosed in adult patients during the time period 1989-2010, with a focus on glioblastoma and low-grade gliomas. METHODS: Data on 21,085 gliomas (excluding grade I tumours) were obtained from the Netherlands Cancer Registry, including tumours of the CNS without pathological confirmation. We calculated the age-standardised incidence rates and the estimated annual percentage change (EAPC) for all glioma subtypes. Crude and relative survival rates were estimated using information on the vital status obtained from the Dutch Municipal Personal Records Database. RESULTS: Incidence of gliomas in adults increased over time, from 4.9 per 100,000 in 1989 to 5.9 in 2010 (EAPC 0.7%, p<0.001). Two thirds were astrocytoma, 10% oligodendroglioma/oligoastrocytoma, 3% ependymoma and 21% were unspecified. Within the group of astrocytic tumours, the proportion of glioblastoma rose, while the proportion of anaplastic and unspecified astrocytoma decreased. Unspecified neoplasms also decreased, but this was significant only after 2005. Over the course of the study period, glioblastoma patients more often received multimodality treatment with chemotherapy concomitant and adjuvant to radiotherapy. The crude two-year survival rate of glioblastoma patients improved significantly, from 5% in the time period 1989-1994 to 15% in 2006-2010, with median survival increasing from 5.5 to 9months. The incidence of low-grade gliomas did not change over time. Survival rates for low-grade oligodendroglial and mixed tumours show a modest improvement. CONCLUSIONS: The incidence rate for the total group of gliomas slightly increased, with a decrease of anaplastic and unspecified tumours and an increase of glioblastoma. Following the introduction of combined chemoradiation, two-year survival rates for glioblastoma significantly improved. Survival improved for low-grade gliomas except for low-grade astrocytic tumours. [less ▲]Detailed reference viewed: 30 (0 ULg)
Prognosis and therapy of tumor-related versus non-tumor-related status epilepticus: a systematic review and meta-analysis.
; ; et al
in BMC neurology (2014), 14
BACKGROUND: Status epilepticus (SE) is a medical emergency with high mortality rates. Of all SE's, 7% are caused by a brain tumor. Clinical guidelines on the management of SE do not make a distinction ... [more ▼]
BACKGROUND: Status epilepticus (SE) is a medical emergency with high mortality rates. Of all SE's, 7% are caused by a brain tumor. Clinical guidelines on the management of SE do not make a distinction between tumor-related SE and SE due to other causes. However, pathophysiological research points towards specific mechanisms of epilepsy in brain tumors. We investigated whether clinical features support a distinct profile of tumor-related SE by looking at measures of severity and response to treatment. METHODS: Systematic review of the literature and meta-analysis of studies on adult SE that report separate data for tumor-related SE and non-tumor-related SE on the following outcomes: short-term mortality, long-term morbidity, duration of SE, and efficacy of anticonvulsant intervention. RESULTS: Fourteen studies on outcome of SE were included. Tumor-related SE was associated with higher mortality than non-tumor-related SE (17.2% versus 11.2%, RR 1.53, 95%-CI 1.24-1.90). After exclusion of patients with hypoxic-ischemic encephalopathy (a group with a known poor prognosis) from the non-tumor-group, the difference in mortality increased (17.2% versus 6.6%; RR 2.78, 95%-CI 2.21 - 3.47). Regarding long-term morbidity and duration of SE there were insufficient data. We did not find studies that systematically compared effects of therapy for SE between tumor- and non-tumor-related SE. CONCLUSIONS: Based on - mostly retrospective - available studies, short-term mortality seems higher in tumor-related SE than in SE due to other causes. Further studies on the outcome and efficacy of different therapeutic regimens in tumor-related SE are needed, to clarify whether tumor-related SE should be regarded as a distinct clinical entity. [less ▲]Detailed reference viewed: 8 (0 ULg)
A role for the canonical nuclear factor-κB pathway in coupling neurotrophin-induced differential survival of developing spiral ganglion neurons
Vandenbosch, Renaud ; ; Robe, Pierre et al
in Frontiers in Cellular Neuroscience (2013), 7Detailed reference viewed: 25 (7 ULg)
Adenovirus-mediated gene therapy with sitimagene ceradenovec followed by intravenous ganciclovir for patients with operable high-grade glioma (ASPECT): a randomised, open-label, phase 3 trial.
; ; et al
in The lancet oncology (2013), 14(9), 823-33
BACKGROUND: Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the ... [more ▼]
BACKGROUND: Besides the use of temozolomide and radiotherapy for patients with favourable methylation status, little progress has been made in the treatment of adult glioblastoma. Local control of the disease by complete removal increases time to progression and survival. We assessed the efficacy and safety of a locally applied adenovirus-mediated gene therapy with a prodrug converting enzyme (herpes-simplex-virus thymidine kinase; sitimagene ceradenovec) followed by intravenous ganciclovir in patients with newly diagnosed resectable glioblastoma. METHODS: For this international, open-label, randomised, parallel group multicentre phase 3 clinical trial, we recruited patients from 38 sites in Europe. Patients were eligible if they were aged 18-70 years, had newly diagnosed supratentorial glioblastoma multiforme amenable to complete resection, and had a Karnofsky score of 70 or more at screening. We used a computer-generated randomisation sequence to allocate patients in a one-to-one ratio (with block sizes of four) to receive either surgical resection of the tumour and intraoperative perilesional injection of sitimagene ceradenovec (1 x 10(12) viral particles) followed by ganciclovir (postoperatively, 5 mg/kg intravenously twice a day) in addition to standard care or resection and standard care alone. Temozolomide, not being standard in all participating countries at the time of the study, was allowed at the discretion of the treating physician. The primary endpoint was a composite of time to death or re-intervention, adjusted for temozolamide use, assessed by intention-to-treat (ITT) analysis. This trial is registered with EudraCT, number 2004-000464-28. FINDINGS: Between Nov 3, 2005, and April 16, 2007, 250 patients were recruited and randomly allocated: 124 to the experimental group and 126 to the standard care group, of whom 119 and 117 patients, respectively, were included in the ITT analyses. Median time to death or re-intervention was longer in the experimental group (308 days, 95% CI 283-373) than in the control group (268 days, 210-313; hazard ratio [HR] 1.53, 95% CI 1.13-2.07; p=0.006). In a subgroup of patients with non-methylated MGMT, the HR was 1.72 (95% CI 1.15-2.56; p=0.008). However, there was no difference between groups in terms of overall survival (median 497 days, 95% CI 369-574 for the experimental group vs 452 days, 95% CI 437-558 for the control group; HR 1.18, 95% CI 0.86-1.61, p=0.31). More patients in the experimental group had one or more treatment-related adverse events those in the control group (88 [71%] vs 51 [43%]). The most common grade 3-4 adverse events were hemiparesis (eight in the experimental group vs three in the control group) and aphasia (six vs two). INTERPRETATION: Our findings suggest that use of sitimagene ceradenovec and ganciclovir after resection can increase time to death or re-intervention in patients with newly diagnosed supratentorial glioblastoma multiforme, although the intervention did not improve overall survival. Locally delivered gene therapy for glioblastoma should be further developed, especially for patients who are unlikely to respond to standard chemotherapy. FUNDING: Ark Therapeutics Ltd. [less ▲]Detailed reference viewed: 17 (10 ULg)
Serial FEM/XFEM-Based Update of Preoperative Brain Images Using Intraoperative MRI
; Noels, Ludovic ; et al
in International Journal of Biomedical Imaging (2012), 2012
Current neuronavigation systems cannot adapt to changing intraoperative conditions over time. To overcome this limitation, we present an experimental end-to-end system capable of updating 3D preoperative ... [more ▼]
Current neuronavigation systems cannot adapt to changing intraoperative conditions over time. To overcome this limitation, we present an experimental end-to-end system capable of updating 3D preoperative images in the presence of brain shift and successive resections. The heart of our system is a nonrigid registration technique using a biomechanical model, driven by the deformations of key surfaces tracked in successive intraoperative images. The biomechanical model is deformed using FEM or XFEM, depending on the type of deformation under consideration, namely brain shift or resection. We describe the operation of our system on two patient cases, each comprising ¯ve intraoperative MR images, and demonstrate that our approach significantly improves the alignment of nonrigidly registered images. [less ▲]Detailed reference viewed: 83 (22 ULg)
Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results.
; ; et al
in Expert Opinion on Investigational Drugs (2012), 21(9), 1391-415
INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to ... [more ▼]
INTRODUCTION: Glioblastoma multiforme is the most common and aggressive primary brain tumor. Valproate has been used as an anti-epileptic drug and mood stabilizer for decades. Recently, it was found to inhibit the proliferation of various cancers including glioblastoma multiforme. AREAS COVERED: We provide a comprehensive review of the mechanisms of action of valproate in gliomas, of its potential side effects and of the published clinical results obtained with this drug in glioblastomas. Valproate inhibits a subset of histone deacetylases and cellular kinases, and affects gene transcription through histone hyperacetylation, DNA hypomethylation and the modulation of several transcription factors. As a result, VPA induces differentiation of glioma cells, can prevent their invasion in surrounding tissues and may inhibit tumor angiogenesis. VPA can also inhibit DNA repair, thereby potentiating cytotoxic treatments such as chemotherapies or radiation therapy. Based on these mechanisms and case reports of glioblastoma remissions following VPA treatment, several clinical studies currently assess the therapeutic potential of VPA in glioma therapy. EXPERT OPINION: The combination of VPA treatment with chemotherapy and radiotherapy in glioblastoma appears a rational option that deserves well-designed prospective clinical trials that assess the efficacy and the molecular characteristics of the responding tumors in these patients. [less ▲]Detailed reference viewed: 12 (0 ULg)
Casein kinase 2 inhibition modulates the DNA damage response but fails to radiosensitize malignant glioma cells.
KROONEN, Jérôme ; Artesi, Maria ; CAPRARO, Valérie et al
in International Journal of Oncology (2012), 41(2), 776-82
Inhibitors of casein kinase 2 (CK2), a regulator of cell proliferation and mediator of the DNA damage response, are being evaluated in clinical trials for the treatment of cancers. Apigenin was capable of ... [more ▼]
Inhibitors of casein kinase 2 (CK2), a regulator of cell proliferation and mediator of the DNA damage response, are being evaluated in clinical trials for the treatment of cancers. Apigenin was capable of inhibiting the activation of CK2 following gamma irradiation in LN18 and U87 malignant glioma cells. Apigenin and siRNA-mediated CK2 protein depletion further inhibited NF-kappaB activation and altered the Tyr68 phosphorylation of Chk2 kinase, a DNA damage response checkpoint kinase, following irradiation. However, CK2 inhibition did not decrease the ability of these glioma cells to repair double-strand DNA breaks, as assessed by COMET assays and gamma-H2Ax staining. Likewise, apigenin and siRNA-induced depletion of CK2 failed to sensitize glioma cells to the cytotoxic effect of 2 to 10 G-rays of gamma irradiation, as assessed by clonogenic assays. These results contrast with those found in other cancer types, and urge to prudence regarding the inclusion of malignant glioma patients in clinical trials that assess the radiosensitizing role of CK2 inhibitors in solid cancers. [less ▲]Detailed reference viewed: 17 (7 ULg)
Multifocal choroid plexus papilloma: a case report.
; Scholtes, Félix ; Robe, Pierre et al
in Clinical neuropathology (2012), 31(6), 430-4
BACKGROUND: Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been ... [more ▼]
BACKGROUND: Multiple choroid plexus papillomas (CPPs) are rare. Usually, they correspond to villous hypertrophy or metastasis occurring during cerebrospinal dissemination. Multiple CPPs have rarely been reported as synchronous tumors. CASE REPORT: Three synchronous CPPs were resected in a 59-year-old female 6 years after their first imaging description. Pathology showed mucus-producing CPP in all 3, 1 of the 3 presenting some signs of atypia. No p53 or hSNF5/INI1 mutation, or signs of polyoma viruses infection were found. CONCLUSION: Although no clear cause for the multifocality was found, the simultaneous presence of the three tumors and their benign histology suggest that they were synchronous and not metastatic. The issue of differentiating synchronous CPPs from metastatic CPP is discussed. [less ▲]Detailed reference viewed: 37 (5 ULg)
3D XFEM-based modeling of retraction for preoperative image update.
; ; Robe, Pierre et al
in Computer aided surgery : official journal of the International Society for Computer Aided Surgery (2011), 16(3), 121-34
Outcomes for neurosurgery patients can be improved by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain deformation. So far ... [more ▼]
Outcomes for neurosurgery patients can be improved by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain deformation. So far, most studies of brain deformation have focused on brain shift, whereas this paper focuses on the brain deformation due to retraction. The heart of our system is a 3D nonrigid registration technique using a biomechanical model driven by the deformations of key surfaces tracked between two intraoperative images. The key surfaces, e.g., the whole-brain region boundary and the lips of the retraction cut, thus deform due to the combination of gravity and retractor deployment. The tissue discontinuity due to retraction is handled via the eXtended Finite Element Method (XFEM), which has the appealing feature of being able to handle arbitrarily shaped discontinuity without any remeshing. Our approach is shown to significantly improve the alignment of intraoperative MRI. [less ▲]Detailed reference viewed: 21 (1 ULg)
Human glioblastoma-initiating cells invade specifically the subventricular zones and olfactory bulbs of mice after striatal injection.
Kroonen, Jérôme ; Nassen, Jessica ; et al
in International Journal of Cancer = Journal International du Cancer (2011), 129(3), 574-585
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs ... [more ▼]
This study reports the subsequent isolation of human glioblatoma cells able to initiate experimental brain tumors, specifically and repeatedly found in the subventricular zones and olfactory bulbs following xenograft in the caudate putamen of immunodeficient mice.In patients with glioblastoma multiforme, recurrence is the rule despite continuous advances in surgery, radiotherapy and chemotherapy. Within these malignant gliomas, glioblastoma stem cells or initiating cells have been recently described and they were shown to be specifically involved in experimental tumorigenesis. In this study, we show that some human glioblastoma cells injected into the striatum of immunodeficient nude mice exhibit a tropism for the subventricular zones. There and similarily to neurogenic stem cells, these subventricular glioblastoma cells were then able to migrate towards the olfactory bulbs. Finally, the glioblastoma cells isolated from the adult mouse subventricular zones and olfactory bulbs display high tumorigenicity when secondary injected in a new mouse brain. Together, these data suggest that neurogenic zones could be a reservoir for particular cancer-initiating cells. [less ▲]Detailed reference viewed: 75 (31 ULg)
NFKBIA Deletion in Glioblastomas.
; ; et al
in New England Journal of Medicine [=NEJM] (2011)
Background Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding ... [more ▼]
Background Amplification and activating mutations of the epidermal growth factor receptor (EGFR) oncogene are molecular hallmarks of glioblastomas. We hypothesized that deletion of NFKBIA (encoding nuclear factor of kappa-light polypeptide gene enhancer in B-cells inhibitor-alpha), an inhibitor of the EGFR-signaling pathway, promotes tumorigenesis in glioblastomas that do not have alterations of EGFR. Methods We analyzed 790 human glioblastomas for deletions, mutations, or expression of NFKBIA and EGFR. We studied the tumor-suppressor activity of NFKBIA in tumor-cell culture. We compared the molecular results with the outcome of glioblastoma in 570 affected persons. Results NFKBIA is often deleted but not mutated in glioblastomas; most deletions occur in nonclassical subtypes of the disease. Deletion of NFKBIA and amplification of EGFR show a pattern of mutual exclusivity. Restoration of the expression of NFKBIA attenuated the malignant phenotype and increased the vulnerability to chemotherapy of cells cultured from tumors with NFKBIA deletion; it also reduced the viability of cells with EGFR amplification but not of cells with normal gene dosages of both NFKBIA and EGFR. Deletion and low expression of NFKBIA were associated with unfavorable outcomes. Patients who had tumors with NFKBIA deletion had outcomes that were similar to those in patients with tumors harboring EGFR amplification. These outcomes were poor as compared with the outcomes in patients with tumors that had normal gene dosages of NFKBIA and EGFR. A two-gene model that was based on expression of NFKBIA and O(6)-methylguanine DNA methyltransferase was strongly associated with the clinical course of the disease. Conclusions Deletion of NFKBIA has an effect that is similar to the effect of EGFR amplification in the pathogenesis of glioblastoma and is associated with comparatively short survival. [less ▲]Detailed reference viewed: 13 (6 ULg)
Enhanced FEM-based Modeling of Brain Shift Deformation in Image-Guided Neurosurgery
; Boman, Romain ; Ponthot, Jean-Philippe et al
in Journal of Computational & Applied Mathematics (2010), 234
We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain ... [more ▼]
We consider the problem of improving outcomes for neurosurgery patients by enhancing intraoperative navigation and guidance. Current navigation systems do not accurately account for intraoperative brain deformation. We focus on the brain shift deformation that occurs just after the opening of the skull and dura. The heart of our system is a nonrigid registration technique using a biomechanical model. We specifically work on two axes: the representation of the structures in the biomechanical model and the evaluation of the surface landmark displacement fields between intraoperative MR images. Using the modified Hausdorff distance as an image similarity measure, we demonstrate that our approach significantly improves the alignment of the intraoperative images. ' 2009 Elsevier B.V. All rights reserved. [less ▲]Detailed reference viewed: 81 (25 ULg)
Intraoperative electrical stimulation in awake craniotomy: methodological aspects of current practice.
; ; et al
in Neurosurgical focus (2010), 28(2), 7
There is increasing evidence that the extent of tumor removal in low-grade glioma surgery is related to patient survival time. Thus, the goal of resecting the largest amount of tumor possible without ... [more ▼]
There is increasing evidence that the extent of tumor removal in low-grade glioma surgery is related to patient survival time. Thus, the goal of resecting the largest amount of tumor possible without leading to permanent neurological sequelae is a challenge for the neurosurgeon. Electrical stimulation of the brain to detect cortical and axonal areas involved in motor, language, and cognitive function and located within the tumor or along its boundaries has become an essential tool in combination with awake craniotomy. Based on a literature review, discussions within the European Low-Grade Glioma Group, and illustrative clinical experience, the authors of this paper provide an overview for neurosurgeons, neurophysiologists, linguists, and anesthesiologists as well as those new to the field about the stimulation techniques currently being used for mapping sensorimotor, language, and cognitive function in awake surgery for low-grade glioma. The paper is intended to help the understanding of these techniques and facilitate a comparison of results between users. [less ▲]Detailed reference viewed: 21 (8 ULg)
Does radiation treatment delay affect survival in glioblastoma
Robe, Pierre ; Nguyen-Khac, Minh-Tuan ; Lenelle, Jacques et al
in Surgical Neurology (2009), 72(5), 519Detailed reference viewed: 74 (11 ULg)
Does radiation treatment delay affect survival in glioblastoma ?
Robe, Pierre ; Nguyen Khac, Minh-Tuan ; Lenelle, Jacques et al
Conference (2009, March 21)Detailed reference viewed: 40 (9 ULg)
Tumor-like MRS and PET findings in a case of radiation-induced brain necrosis, away from any tumor: an intringuing case report
Nguyen Khac, Minh-Tuan ; Hustinx, Roland ; Deprez, Manuel et al
Conference (2009, March 21)Detailed reference viewed: 35 (6 ULg)
Monosomy of chromosome 10 associated with dysregulation of epidermal growth factor signaling in glioblastomas.
; ; et al
in JAMA : Journal of the American Medical Association (2009), 302(3), 276-89
CONTEXT: Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for ... [more ▼]
CONTEXT: Glioblastomas--uniformly fatal brain tumors--often have both monosomy of chromosome 10 and gains of the epidermal growth factor receptor (EGFR) gene locus on chromosome 7, an association for which the mechanism is poorly understood. OBJECTIVES: To assess whether coselection of EGFR gains on 7p12 and monosomy 10 in glioblastomas promotes tumorigenic epidermal growth factor (EGF) signaling through loss of the annexin A7 (ANXA7) gene on 10q21.1-q21.2 and whether ANXA7 acts as a tumor suppressor gene by regulating EGFR in glioblastomas. DESIGN, SETTING, AND PATIENTS: Multidimensional analysis of gene, coding sequence, promoter methylation, messenger RNA (mRNA) transcript, protein data for ANXA7 (and EGFR), and clinical patient data profiles of 543 high-grade gliomas from US medical centers and The Cancer Genome Atlas pilot project (made public 2006-2008; and unpublished, tumors collected 2001-2008). Functional analyses using LN229 and U87 glioblastoma cells. MAIN OUTCOME MEASURES: Associations among ANXA7 gene dosage, coding sequence, promoter methylation, mRNA transcript, and protein expression. Effect of ANXA7 haploinsufficiency on EGFR signaling and patient survival. Joint effects of loss of ANXA7 and gain of EGFR expression on tumorigenesis. RESULTS: Heterozygous ANXA7 gene deletion is associated with significant loss of ANXA7 mRNA transcript expression (P = 1 x 10(-15); linear regression) and a reduction (mean [SEM]) of 91.5% (2.3%) of ANXA7 protein expression compared with ANXA7 wild-type glioblastomas (P = .004; unpaired t test). ANXA7 loss of function stabilizes the EGFR protein (72%-744% increase in EGFR protein abundance) and augments EGFR transforming signaling in glioblastoma cells. ANXA7 haploinsufficiency doubles tumorigenic potential of glioblastoma cells, and combined ANXA7 knockdown and EGFR overexpression promotes tumorigenicity synergistically. The heterozygous loss of ANXA7 in approximately 75% of glioblastomas in the The Cancer Genome Atlas plus infrequency of ANXA7 mutation (approximately 6% of tumors) indicates its role as a haploinsufficiency gene. ANXA7 mRNA transcript expression, dichotomized at the median, associates with patient survival in 191 glioblastomas (log-rank P = .008; hazard ratio [HR], 0.667; 95% confidence interval [CI], 0.493-0.902; 46.9 vs 74.8 deaths/100 person-years for high vs low ANXA7 mRNA expression) and with a separate group of 180 high-grade gliomas (log-rank P = .00003; HR, 0.476; 95% CI, 0.333-0.680; 21.8 vs 50.0 deaths/100 person-years for high vs low ANXA7 mRNA expression). Deletion of the ANXA7 gene associates with poor patient survival in 189 glioblastomas (log-rank P = .042; HR, 0.686; 95% CI, 0.476-0.989; 54.0 vs 80.1 deaths/100 person-years for wild-type ANXA7 vs ANXA7 deletion). CONCLUSION: Haploinsufficiency of the tumor suppressor ANXA7 due to monosomy of chromosome 10 provides a clinically relevant mechanism to augment EGFR signaling in glioblastomas beyond that resulting from amplification of the EGFR gene. [less ▲]Detailed reference viewed: 23 (1 ULg)