Variations in the genomic profiles and clinical behavior of meningioma by racial and ethnic group.

OBJECTIVE: The influence of socioeconomic factors on racial disparities among patients with sporadic meningiomas is well established, yet other potential causative factors warrant further exploration. The authors of this study aimed to determine whether there is significant variation in the genomic profile of meningiomas among patients of different races and ethnicities and its correlation with clinical outcomes. METHODS: The demographic, genomic, and clinical data of patients aged 18 years and older who had undergone surgery for sporadic meningioma between September 2008 and November 2021 were analyzed. Statistical analyses were performed to detect differences across all racial/ethnic groups, as were direct comparisons between Black and non-Black groups plus Hispanic and non-Hispanic groups. RESULTS: This study included 460 patients with intracranial meningioma. Hispanic patients were significantly younger at surgery (53.9 vs 60.2 years, p = 0.0006) and more likely to show symptoms. Black patients had a higher incidence of anterior skull base tumors (OR 3.2, 95% CI 1.7-6.3, p = 0.0008) and somatic hedgehog mutations (OR 5.3, 95% CI 1.6-16.6, p = 0.003). Hispanics were less likely to exhibit the aggressive genomic characteristic of chromosome 1p deletion (OR 0.28, 95% CI 0.07-1.2, p = 0.06) and displayed higher rates of TRAF7 somatic driver mutations (OR 2.96 95% CI 1.1-7.8, p = 0.036). Black patients had higher rates of recurrence (OR 2.6, 95% CI 1.3-5.2, p = 0.009) and shorter progression-free survival (PFS; HR 2.9, 95% CI 1.6-5.4, p = 0.002) despite extents of resection (EORs) similar to those of non-Black patients (p = 0.745). No significant differences in overall survival were observed among groups. CONCLUSIONS: Despite similar EORs, Black patients had worse clinical outcomes following meningioma resection, characterized by a higher prevalence of somatic hedgehog mutations, increased recurrence rates, and shorter PFS. Meanwhile, Hispanic patients had less aggressive meningiomas, a predisposition for TRAF7 mutations, and no difference in PFS. These findings could inform the care and treatment strategies for meningiomas, and they establish the foundation for future studies focusing on the genomic origins of these observed differences.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas.

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway  in neoplasia.

The clinical and genomic features of seizures in meningiomas.

Meningiomas are the most common central nervous system tumors. Although these tumors are extra-axial, a relatively high proportion (10%-50%) of meningioma patients have seizures that can substantially impact the quality of life. Meningiomas are believed to cause seizures by inducing cortical hyperexcitability that results from mass effect and cortical irritation, brain invasion, or peritumoral brain edema. In general, meningiomas that are associated with seizures have aggressive features, with risk factors including atypical histology, brain invasion, and higher tumor grade. Somatic NF2 mutated meningiomas are associated with preoperative seizures, but the effect of the driver mutation is mediated through atypical features. While surgical resection is effective in controlling seizures in most patients with meningioma-related epilepsy, a history of seizures and uncontrolled seizures prior to surgery is the most significant predisposing factor for persistent postoperative seizures. Subtotal resection (STR) and relatively larger residual tumor volume are positive predictors of postoperative seizures. Other factors, including higher WHO grade, peritumoral brain edema, and brain invasion, are inconsistently associated with postoperative seizures, suggesting they might be crucial in the development of an epileptogenic focus, but do not appear to play a substantial role after seizure activity has been established. Herein, we review and summarize the current literature surrounding meningioma-related epilepsy and underscore the interaction of multiple factors that relate to seizures in patients with meningioma.

Contribution of Somatic Ras/Raf/Mitogen-Activated Protein Kinase Variants in the Hippocampus in Drug-Resistant Mesial Temporal Lobe Epilepsy.

Importance: Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy subtype and is often refractory to antiseizure medications. While most patients with MTLE do not have pathogenic germline genetic variants, the contribution of postzygotic (ie, somatic) variants in the brain is unknown. Objective: To test the association between pathogenic somatic variants in the hippocampus and MTLE. Design, Setting, and Participants: This case-control genetic association study analyzed the DNA derived from hippocampal tissue of neurosurgically treated patients with MTLE and age-matched and sex-matched neurotypical controls. Participants treated at level 4 epilepsy centers were enrolled from 1988 through 2019, and clinical data were collected retrospectively. Whole-exome and gene-panel sequencing (each genomic region sequenced more than 500 times on average) were used to identify candidate pathogenic somatic variants. A subset of novel variants was functionally evaluated using cellular and molecular assays. Patients with nonlesional and lesional (mesial temporal sclerosis, focal cortical dysplasia, and low-grade epilepsy-associated tumors) drug-resistant MTLE who underwent anterior medial temporal lobectomy were eligible. All patients with available frozen tissue and appropriate consents were included. Control brain tissue was obtained from neurotypical donors at brain banks. Data were analyzed from June 2020 to August 2022. Exposures: Drug-resistant MTLE. Main Outcomes and Measures: Presence and abundance of pathogenic somatic variants in the hippocampus vs the unaffected temporal neocortex. Results: Of 105 included patients with MTLE, 53 (50.5%) were female, and the median (IQR) age was 32 (26-44) years; of 30 neurotypical controls, 11 (36.7%) were female, and the median (IQR) age was 37 (18-53) years. Eleven pathogenic somatic variants enriched in the hippocampus relative to the unaffected temporal neocortex (median [IQR] variant allele frequency, 1.92 [1.5-2.7] vs 0.3 [0-0.9]; P = .01) were detected in patients with MTLE but not in controls. Ten of these variants were in PTPN11, SOS1, KRAS, BRAF, and NF1, all predicted to constitutively activate Ras/Raf/mitogen-activated protein kinase (MAPK) signaling. Immunohistochemical studies of variant-positive hippocampal tissue demonstrated increased Erk1/2 phosphorylation, indicative of Ras/Raf/MAPK activation, predominantly in glial cells. Molecular assays showed abnormal liquid-liquid phase separation for the PTPN11 variants as a possible dominant gain-of-function mechanism. Conclusions and Relevance: Hippocampal somatic variants, particularly those activating Ras/Raf/MAPK signaling, may contribute to the pathogenesis of sporadic, drug-resistant MTLE. These findings may provide a novel genetic mechanism and highlight new therapeutic targets for this common indication for epilepsy surgery.

Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas.

OBJECTIVE: Mutations in NF2 are the most common somatic driver mutation in sporadic meningiomas. NF2 mutant meningiomas preferentially arise along the cerebral convexities-however, they can also be found in the posterior fossa. The authors investigated whether NF2 mutant meningiomas differ in clinical and genomic features based on their location relative to the tentorium. METHODS: Clinical and whole exome sequencing (WES) data for patients who underwent resection of sporadic NF2 mutant meningiomas were reviewed and analyzed. RESULTS: A total of 191 NF2 mutant meningiomas were included (165 supratentorial, 26 infratentorial). Supratentorial NF2 mutant meningiomas were significantly associated with edema (64.0% vs 28.0%, p < 0.001); higher grade-i.e., WHO grade II or III (41.8% vs 3.9%, p < 0.001); elevated Ki-67 (55.0% vs 13.6%, p < 0.001); and larger volume (mean 45.5 cm3 vs 14.9 cm3, p < 0.001). Furthermore, supratentorial tumors were more likely to harbor the higher-risk feature of chromosome 1p deletion (p = 0.038) and had a larger fraction of the genome altered with loss of heterozygosity (p < 0.001). Infratentorial meningiomas were more likely to undergo subtotal resection than supratentorial tumors (37.5% vs 15.8%, p = 0.021); however, there was no significant difference in overall (p = 0.2) or progression-free (p = 0.4) survival. CONCLUSIONS: Supratentorial NF2 mutant meningiomas are associated with more aggressive clinical and genomic features as compared with their infratentorial counterparts. Although infratentorial tumors have higher rates of subtotal resection, there is no associated difference in survival or recurrence. These findings help to better inform surgical decision-making in the management of NF2 mutant meningiomas based on location, and may guide postoperative management of these tumors.

A systematic review and individual participant data meta-analysis of gonadal steroid hormone receptors in meningioma.

OBJECTIVE: The relationship between patient and meningioma characteristics and hormone receptors (HRs) of progesterone, estrogen, and androgen remains poorly defined despite literature suggesting that meningiomas are sensitive to gonadal steroid hormones. Therefore, the authors sought to collect and compare data on this topic by performing a systematic review and meta-analysis of reported studies of HR status in meningiomas. METHODS: A MEDLINE PubMed literature review conducted for articles published between January 1, 1951, and December 31, 2020, resulted in 634 unduplicated articles concerning meningiomas and HRs. There were 114 articles that met the criteria of detailed detection protocols for progesterone receptor (PR), estrogen receptor (ER), and/or androgen receptor (AR) using immunohistochemistry (IHC) or ligand-binding (LB) assays and simultaneous reporting of HR status with at least one variable among age, sex, histology, location, grade, or recurrence. Between-study heterogeneity and risk of bias were evaluated using graphical and statistical methods. The authors performed a multilevel meta-analysis using random-effects modeling on aggregated data (n = 4447) and individual participant data (n = 1363) with subgroup results summarized as pooled effects. A mixed-effects meta-regression using individual participant data was performed to analyze independently associated variables. RESULTS: The 114 selected articles included data for 5810 patients with 6092 tumors analyzed to determine the expression of three HRs in human meningiomas: PRs, ARs, and ERs. The proportions of HR+ meningiomas were estimated to be 0.76 (95% CI 0.72-0.80) for PR+ and 0.50 (95% CI 0.33-0.66) for AR+ meningiomas. ER+ meningioma detection varied depending on the measurement method used and was 0.06 (95% CI 0.03-0.10) with IHC and 0.11 (95% CI 0.06-0.20) with LB assays. There were associations between age and PR and ER expression that varied between male and female patients. PR+ and AR+ were more common in female patients (OR 1.84, 95% CI 1.47-2.29 for PR and OR 4.16, 95% CI 1.62-10.68 for AR). Additionally, PR+ meningiomas were enriched in skull base locations (OR 1.89, 95% CI 1.03-3.48) and meningothelial histology (OR 1.86, 95% CI 1.23-2.81). A meta-regression showed that PR+ was independently associated with age (OR 1.11 95% CI 1.09-1.13; p < 0.0001) and WHO grade I tumors (OR 8.09, 95% CI 3.55-18.44; p < 0.0001). ER+ was negatively associated with meningothelial histology (OR 0.94, 95% CI 0.86-0.98; p = 0.044) and positively associated with convexity location (OR 1.12, 95% CI 1.05-1.18; p = 0.0003). CONCLUSIONS: The association between HRs and meningioma features has been investigated but unexplained for decades. In this study the authors demonstrated that HR status has a strong association with known meningioma features, including WHO grade, age, female sex, histology, and anatomical location. Identifying these independent associations allows for a better understanding of meningioma heterogeneity and provides a foundation for revisiting targeted hormonal therapy in meningioma on the basis of proper patient stratification according to HR status.

Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.

Multiomic analyses implicate a neurodevelopmental program in the pathogenesis of cerebral arachnoid cysts.

Cerebral arachnoid cysts (ACs) are one of the most common and poorly understood types of developmental brain lesion. To begin to elucidate AC pathogenesis, we performed an integrated analysis of 617 patient-parent (trio) exomes, 152,898 human brain and mouse meningeal single-cell RNA sequencing transcriptomes and natural language processing data of patient medical records. We found that damaging de novo variants (DNVs) were highly enriched in patients with ACs compared with healthy individuals (P = 1.57 × 10-33). Seven genes harbored an exome-wide significant DNV burden. AC-associated genes were enriched for chromatin modifiers and converged in midgestational transcription networks essential for neural and meningeal development. Unsupervised clustering of patient phenotypes identified four AC subtypes and clinical severity correlated with the presence of a damaging DNV. These data provide insights into the coordinated regulation of brain and meningeal development and implicate epigenomic dysregulation due to DNVs in AC pathogenesis. Our results provide a preliminary indication that, in the appropriate clinical context, ACs may be considered radiographic harbingers of neurodevelopmental pathology warranting genetic testing and neurobehavioral follow-up. These data highlight the utility of a systems-level, multiomics approach to elucidate sporadic structural brain disease.

Vascular steal and associated intratumoral aneurysms in highly vascular brain tumors: illustrative case.

BACKGROUND: Intratumoral aneurysms in highly vascular brain tumors can complicate resection depending on their location and feasibility of proximal control. Seemingly unrelated neurological symptoms may be from vascular steal that can help alert the need for additional vascular imaging and augmenting surgical strategies. OBSERVATIONS: A 29-year-old female presented with headaches and unilateral blurred vision, secondary to a large right frontal dural-based lesion with hypointense signal thought to represent calcifications. Given these latter findings and clinical suspicion for a vascular steal phenomenon to explain the blurred vision, computed tomography angiography was obtained, revealing a 4 × 2-mm intratumoral aneurysm. Diagnostic cerebral angiography confirmed this along with vascular steal by the tumor from the right ophthalmic artery. The patient underwent endovascular embolization of the intratumoral aneurysm, followed by open tumor resection in the same setting without complication, minimal blood loss, and improvement in her vision. LESSONS: Understanding the blood supply of any tumor, but highly vascular ones in particular, and the relationship with normal vasculature is undeniably important in avoiding potentially dangerous situations and optimizing maximal safe resection. Recognition of highly vascular tumors should prompt thorough understanding of the vascular supply and relationship of intracranial vasculature with consideration of endovascular adjuncts when appropriate.

Hormone therapies in meningioma-where are we?

INTRODUCTION: Meningiomas are associated with several gonadal steroid hormone-related risk factors and demonstrate a predominance in females. These associations led to investigations of the role that hormones may have on meningioma growth and development. While it is now accepted that most meningiomas express progesterone and somatostatin receptors, the conclusion for other receptors has been less definitive. METHODS: We performed a review of what is known regarding the relationship between hormones and meningiomas in the published literature. Furthermore, we reviewed clinical trials related to hormonal agents in meningiomas using MEDLINE PubMed, Scopus, and the NIH clinical trials database. RESULTS: We identify that all steroid-hormone trials lacked receptor identification or positive receptor status in the majority of patients. In contrast, four out of five studies involving somatostatin analogs used positive receptor status as part of the inclusion criteria. CONCLUSIONS: Several clinical trials have recently been completed or are now underway using somatostatin analogs in combination with other therapies that appear promising, but a reevaluation of hormone-based monotherapy is warranted. Synthesizing this evidence, we clarify the remaining questions and present future directions for the study of the biological role and therapeutic potential of hormones in meningioma and discuss how the stratification of patients using features such as grade, receptor status, and somatic mutations, might be used for future trials to select patients most likely to benefit from specific therapies.

Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion.

BACKGROUND: Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from 10 patients. METHODS: Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from 10 GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using hematoxylin and eosin and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model. RESULTS: At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to postoperative recurrence and is highly co-expressed with CD44 in invasive GBM samples. CONCLUSIONS: Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.

Interferon-γ resistance and immune evasion in glioma develop via Notch-regulated co-evolution of malignant and immune cells.

Immune surveillance is critical to prevent tumorigenesis. Gliomas evade immune attack, but the underlying mechanisms remain poorly understood. We show that glioma cells can sustain growth independent of immune system constraint by reducing Notch signaling. Loss of Notch activity in a mouse model of glioma impairs MHC-I and cytokine expression and curtails the recruitment of anti-tumor immune cell populations in favor of immunosuppressive tumor-associated microglia/macrophages (TAMs). Depletion of T cells simulates Notch inhibition and facilitates tumor initiation. Furthermore, Notch-depleted glioma cells acquire resistance to interferon-γ and TAMs re-educating therapy. Decreased interferon response and cytokine expression by human and mouse glioma cells correlate with low Notch activity. These effects are paralleled by upregulation of oncogenes and downregulation of quiescence genes. Hence, suppression of Notch signaling enables gliomas to evade immune surveillance and increases aggressiveness. Our findings provide insights into how brain tumor cells shape their microenvironment to evade immune niche control.

Genomic profiling of sporadic multiple meningiomas.

BACKGROUND: Multiple meningiomas (MMs) rarely occur sporadically. It is unclear whether each individual tumor in a single patient behaves similarly. Moreover, the molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood. METHODS: Patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas were included. Unbiased, comprehensive next generation sequencing was performed, and relevant clinical data was analyzed. RESULTS: Fifteen meningiomas and one dural specimen from six patients were included. The majority of tumors (12/15) were WHO Grade I; one patient had bilateral MMs, one of which was Grade II, while the other was Grade I. We found 11/15 of our cohort specimens were of NF2-loss subtype. Meningiomas from 5/6 patients had a monoclonal origin, with the tumor from the remaining patient showing evidence for independent clonal formation. We identified a novel case of non-NF2 mutant MM with monoclonal etiology. MMs due to a monoclonal origin did not always display a homogenous genomic profile, but rather exhibited heterogeneity due to branching evolution. CONCLUSIONS: Both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.

The integrated multiomic diagnosis of sporadic meningiomas: a review of its clinical implications.

INTRODUCTION: Meningiomas are generally considered "benign," however, these tumors can demonstrate variability in behavior and a surprising aggressiveness with elevated rates of recurrence. The advancement of next-generation molecular technologies have led to the understanding of the genomic and epigenomic landscape of meningiomas and more recent correlations with clinical characteristics and behavior. METHODS: Based on a thorough review of recent peer-reviewed publications (PubMed) and edited texts, we provide a molecular overview of meningiomas with a focus on relevant clinical implications. RESULTS: The identification of specific somatic driver mutations has led to the classification of several major genomic subgroups, which account for more than 80% of sporadic meningiomas, and can be distinguished using noninvasive clinical variables to help guide management decisions. Other somatic genomic modifications, including non-coding alterations and copy number variations, have also been correlated with tumor characteristics. Furthermore, epigenomic modifications in meningiomas have recently been described, with DNA methylation being the most widely studied and potentially most clinically relevant. Based on these molecular insights, several clinical trials are currently underway in an effort to establish effective medical therapeutic options for meningioma. CONCLUSION: As we enhance our multiomic understanding of meningiomas, our ability to care for patients with these tumors will continue to improve. Further biological insights will lead to additional progress in precision medicine for meningiomas.

Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas.

PURPOSE: As sphenoid wing meningiomas (SWMs) are associated with varying degrees of bony involvement, we sought to understand potential relationships between genomic subgroup and this feature. METHODS: Patients treated at Yale-New Haven Hospital for SWM were reviewed. Genomic subgroup was determined via whole exome sequencing, while the extent of bony involvement was radiographically classified as no bone invasion (Type I), hyperostosis only (Type II), tumor invasion only (Type III), or both hyperostosis and tumor invasion (Type IV). Among additional clinical variables collected, a subset of tumors was identified as spheno-orbital meningiomas (SOMs). Machine-learning approaches were used to predict genomic subgroups based on pre-operative clinical features. RESULTS: Among 64 SWMs, 53% had Type-II, 9% had Type-III, and 14% had Type-IV bone involvement; nine SOMs were identified. Tumors with invasion (i.e., Type III or IV) were more likely to be WHO grade II (p: 0.028). Additionally, tumors with invasion were nearly 30 times more likely to harbor NF2 mutations (OR 27.6; p: 0.004), while hyperostosis only were over 4 times more likely to have a TRAF7 mutation (OR 4.5; p: 0.023). SOMs were a significant predictor of underlying TRAF7 mutation (OR 10.21; p: 0.004). CONCLUSIONS: SWMs with invasion into bone tend to be higher grade and are more likely to be NF2 mutated, while SOMs and those with hyperostosis are associated with TRAF7 variants. Pre-operative prediction of molecular subtypes based on radiographic bony characteristics may have significant biological and clinical implications based on known recurrence patterns associated with genomic drivers and grade.

Targeting the CSF1/CSF1R axis is a potential treatment strategy for malignant meningiomas.

BACKGROUND: Malignant meningiomas are fatal and lack effective therapy. As M2 macrophages are the most prevalent immune cell type in human meningiomas, we hypothesized that normalizing this immunosuppressive population would be an effective treatment strategy. METHODS: We used CIBERSORTx to examine the proportions of 22 immune subsets in human meningiomas. We targeted the colony-stimulating factor 1 (CSF1) or CSF1 receptor (CSF1R) axis, an important regulator of macrophage phenotype, using monoclonal antibodies (mAbs) in a novel immunocompetent murine model (MGS1) for malignant meningioma. RNA sequencing (RNA-seq) was performed to identify changes in gene expression in the tumor microenvironment (TME). Mass cytometry was used to delineate changes in immune subsets after treatment. We measured patients' plasma CSF1 levels using ELISA and CSF1R expression using multiplex quantitative immunofluorescence in a human meningioma tissue microarray. RESULTS: Human meningiomas are heavily enriched for immunosuppressive myeloid cells. MGS1 recapitulates the TME of human meningiomas, including an abundance of myeloid cells, a paucity of infiltrating T cells, and low programmed death ligand 1 (PD-L1) expression. Treatment of murine meningiomas with anti-CSF1/CSF1R, but not programmed cell death receptor 1 (PD-1), mAbs abrogate tumor growth. RNA-seq and mass cytometry analyses reveal a myeloid cell reprogramming with limited effect on T cells in the TME. CSF1 plasma levels are significantly elevated in human patients, and CSF1R is highly expressed on CD163+ macrophages within the human TME. CONCLUSION: Our findings suggest that anti-CSF1/CSF1R antibody treatment may be an effective normalization cancer immunotherapy for malignant meningiomas.

Genetically Determined Smoking Behavior and Risk of Nontraumatic Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH. METHODS: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate (P<5×10-8) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods. RESULTS: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20-1.21]; P<0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03-1.17]; P=0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15-2.31]; P=0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13-2.17]; P=0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06-2.86]; P=0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P=0.39; MR Pleiotropy Residual Sum and Outlier global test P=0.69). CONCLUSIONS: These findings provide evidence for a causal link between smoking and the risk of SAH.