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Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology. Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2 /Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients. DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features.

Meningiomas are stratified according to tumor grade and extent of resection, often in isolation of other clinical variables. Here, we use machine learning (ML) to integrate demographic, clinical, radiographic and pathologic data to develop predictive models for meningioma outcomes. We developed a comprehensive database containing information from 235 patients who underwent surgery for 257 meningiomas at a single institution from 1990 to 2015. The median follow-up was 4.3 years, and resection specimens were re-evaluated according to current diagnostic criteria, revealing 128 WHO grade I, 104 grade II and 25 grade III meningiomas. A series of ML algorithms were trained and tuned by nested resampling to create models based on preoperative features, conventional postoperative features, or both. We compared different algorithms' accuracy as well as the unique insights they offered into the data. Machine learning models restricted to preoperative information, such as patient demographics and radiographic features, had similar accuracy for predicting local failure (AUC = 0.74) or overall survival (AUC = 0.68) as models based on meningioma grade and extent of resection (AUC = 0.73 and AUC = 0.72, respectively). Integrated models incorporating all available demographic, clinical, radiographic and pathologic data provided the most accurate estimates (AUC = 0.78 and AUC = 0.74, respectively). From these models, we developed decision trees and nomograms to estimate the risks of local failure or overall survival for meningioma patients. Clinical information has been historically underutilized in the prediction of meningioma outcomes. Predictive models trained on preoperative clinical data perform comparably to conventional models trained on meningioma grade and extent of resection. Combination of all available information can help stratify meningioma patients more accurately.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2. The molecular mechanisms underlying malignant transformation of the Schwann lineage in Schwann cell tumours remain to be explored. Here, the authors suggest that NF2 inactivation leads to PAK activation leading to NF1-mutant Schwann cell tumour de-differentiation and resistance to selumetinib.

Background Approximately 20–30% of patients with metastatic breast cancer (MBC) develop brain metastases (BM) over the course of their disease. It is critical to better understand risk factors and survival outcomes in these patients, including those treated in the modern treatment era. Methods We identified patients with MBC and BM diagnosed between 1997 and 2024 at our institution. Review of medical records was completed to identify key demographic, clinical, and survival characteristics. Results We identified 507 patients with MBC and BMs with the following subtypes: HR+/HER2- ( n  = 184, 36.3%), HER2+ ( n  = 197, 38.9%), and triple negative breast cancer (TNBC; n  = 126, 24.9%). Median real-world overall survival (rwOS) from the diagnosis of first BM to death was 21.6 months with the longest median rwOS in patients with HER2+ disease (31.0 months) vs. patients with HR+/HER2- (19.6 months) or TNBC (12.8 months) ( p  < 0.001). By date of BM diagnosis 1997–2014 vs. 2015–2024 (divided by ~ 50% of patients in each time period), patients with HER2+ and TNBC lived longer in the more modern cohort compared to prior years (HER2+: 41.2 vs. 26.2 months, p  = 0.002; TNBC: 14.9 vs. 7.0 p  = 0.020). There was no statistically significant difference for patients with HR+/HER2- disease (16.5 vs. 21.6, p  = 0.089). On multivariable analysis, HER2+ disease (HR 0.64, 95% CI 0.50–0.81, p  < 0.001), BM surgical resection (HR 0.67, 95% CI 0.51–0.87, p  = 0.002), and BM diagnosis after 2014 (HR 0.77, CI 0.63–0.95, p  = 0.015) were associated with longer survival. TNBC (HR 1.46, CI 1.12–1.89, p  = 0.004), having 6–10 BMs at baseline (HR 1.66, CI 1.14–2.42, p  = 0.009), extracranial MBC (HR 1.34 CI 1.02–1.76, p  = 0.034) and development of leptomeningeal disease (HR 1.41, CI 1.11–1.80, p  = 0.005) were associated with shorter survival. Conclusion In a cohort of > 500 patients with MBC BMs spanning > 25 years, median rwOS from the diagnosis of first BM was almost two years. Favorable factors included HER2+ disease, BM surgical resection, and diagnosis after 2014. Poor prognostic factors included TNBC, having 6–10 BMs, extracranial MBC, and development of LMD. Patients with HER2+ and TN MBC with BM had improved rwOS in a more modern cohort; this was not seen for HR+/HER2- patients, representing an area of ongoing unmet clinical need.

Background A significant proportion of patients with advanced cancer undergo palliative radiotherapy (RT) within their last 30 days of life. This study characterizes palliative RT at our institution and aims to identify patients who may experience limited benefit from RT due to imminent mortality. Methods Five hundred and-eighteen patients treated with external beam RT to a site of metastatic disease between 2012 and 2016 were included. Mann-Whitney U and chi-squared tests were used to identify factors associated with RT within 30 days of death (D 30 RT). Results Median age at RT was 63 years (IQR 54–71). Median time from RT to death was 74 days (IQR 33–174). One hundred and twenty-five patients (24%) died within 30 days of RT. D 30 RT was associated with older age at RT (64 vs. 62 years, p  = 0.04), shorter interval since diagnosis (14 vs. 31 months, p  <  0.001), liver metastasis ( p  = 0.02), lower KPS (50 vs. 70, p  <  0.001), lower BMI (22 vs. 24, p  = 0.001), and inpatient status at consult (56% vs. 26%, p  < 0.001). Patients who died within 30 days of RT were less likely to have hospice involved in their care (44% vs. 71%, p  = 0.001). D 30 RT was associated with higher Chow and TEACHH scores at consult ( p  < 0.001 for both). Conclusions Twenty-four percent of patients received palliative RT within 30 days of death. Additional tools are necessary to help physicians identify patients who would benefit from short treatment courses or alternative interventions to maximize quality at the end of life.

The cellular response to DNA damage is mediated through multiple pathways that regulate and coordinate DNA repair, cell cycle arrest, and cell death. We show that the DNA damage response (DDR) induced by ionizing radiation (IR) is coordinated in breast cancer cells by selective mRNA translation mediated by high levels of translation initiation factor eIF4G1 (eukaryotic initiation factor 4γ1). Increased expression of eIF4G1, common in breast cancers, was found to selectively increase translation of mRNAs involved in cell survival and the DDR, preventing autophagy and apoptosis [ Survivin , hypoxia inducible factor 1α ( HIF1 α ), X-linked inhibitor of apoptosis ( XIAP )], promoting cell cycle arrest [growth arrest and DNA damage protein 45a ( GADD45a ), protein 53 ( p53 ), ATR-interacting protein ( ATRIP ), Check point kinase 1 ( Chk1 )] and DNA repair [p53 binding protein 1 ( 53BP1 ), breast cancer associated proteins 1, 2 ( BRCA1/2 ), Poly-ADP ribose polymerase ( PARP ), replication factor c2–5 ( Rfc2-5 ), ataxia telangiectasia mutated gene 1 ( ATM ), meiotic recombination protein 11 ( MRE-11 ), and others]. Reduced expression of eIF4G1, but not its homolog eIF4G2, greatly sensitizes cells to DNA damage by IR, induces cell death by both apoptosis and autophagy, and significantly delays resolution of DNA damage foci with little reduction of overall protein synthesis. Although some mRNAs selectively translated by higher levels of eIF4G1 were found to use internal ribosome entry site (IRES)-mediated alternate translation, most do not. The latter group shows significantly reduced dependence on eIF4E for translation, facilitated by an enhanced requirement for eIF4G1. Increased expression of eIF4G1 therefore promotes specialized translation of survival, growth arrest, and DDR mRNAs that are important in cell survival and DNA repair following genotoxic DNA damage.

Glioblastoma is a clinically and molecularly heterogeneous disease, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 consecutive primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a unique subgroup (2%, 9/459) defined by somatic hypermutation and DNA replication repair deficiency due to biallelic inactivation of a canonical mismatch repair gene. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining allele, consistent with glioblastomas arising due to underlying Lynch syndrome. A subset of tumors had accompanying proofreading domain mutations in the DNA polymerase POLE and resultant “ultrahypermutation”. The median age at diagnosis was 50 years (range 27–78), compared with 63 years for the other 450 patients with conventional glioblastoma ( p  < 0.01). All tumors had histologic features of the giant cell variant of glioblastoma. They lacked EGFR amplification, lacked combined trisomy of chromosome 7 plus monosomy of chromosome 10, and only rarely had TERT promoter mutation or CDKN2A homozygous deletion, which are hallmarks of conventional IDH-wildtype glioblastoma. Instead, they harbored frequent inactivating mutations in TP53 , NF1 , PTEN , ATRX , and SETD2 and recurrent activating mutations in PDGFRA . DNA methylation profiling revealed they did not align with known reference adult glioblastoma methylation classes, but instead had unique globally hypomethylated epigenomes and mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A”. Five patients were treated with immune checkpoint blockade, four of whom survived greater than 3 years. The median overall survival was 36.8 months, compared to 15.5 months for the other 450 patients ( p  < 0.001). We conclude that “De novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype in the adult population that may benefit from prospective identification and treatment with immune checkpoint blockade.

Purpose To report patient outcomes and local tumor control rates in a cohort of patients with biopsy-proven HER-2 positive breast cancer treated with stereotactic radiosurgery (SRS) for brain metastases (BM). Methods This international, retrospective, multicenter study, included 195 female patients with 1706 SRS-treated BM. Radiologic and clinical outcomes after SRS were determined and prognostic factors identified. Results At SRS, median patient age was 55 years [interquartile range (IQR) 47.6–62.0], and 156 (80%) patients had KPS ≥ 80. The median tumor volume was 0.1 cm 3 (IQR 0.1–0.5) and the median prescription dose was 16 Gy (IQR 16–18). Local tumor control (LTC) rate was 98%, 94%, 93%, 90%, and 88% at six-, 12-, 24-, 36- and 60-months post-SRS, respectively. On multivariate analysis, tumor volume ( p  = < 0.001) and concurrent pertuzumab ( p  = 0.02) improved LTC. Overall survival (OS) rates at six-, 12-, 24-, 36-, 48-, and 60-months were 90%, 69%, 46%, 27%, 22%, and 18%, respectively. Concurrent pertuzumab improved OS ( p  = 0.032). In this patient subgroup, GPA scores ≥ 2.5 ( p  = 0.038 and p  = 0.003) and rare primary tumor histologies ( p  = 0.01) were associated with increased and decreased OS, respectively. Asymptomatic adverse radiation events (ARE) occurred in 27 (14.0%) and symptomatic ARE in five (2.6%) patients. Invasive lobular carcinoma primary ( p  = 0.042) and concurrent pertuzumab ( p  < 0.001) conferred an increased risk for overall but not for symptomatic ARE. Conclusion SRS affords effective LTC for selected patients with BM from HER-2 positive breast cancer. Concurrent pertuzumab improved LTC and OS but at the same time increased the risk for overall, but not symptomatic, ARE.