Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

Du, Ziwei; Abedalthagafi, Malak; Aizer, Ayal A.; McHenry, Allison; Sun, Heather H.; Bray, Mark‐Anthony; Viramontes, Omar; Machaidze, Revaz; Brastianos, Priscilla K.; Reardon, David A.; Dunn, Ian F.; Freeman, Gordon J.; Ligon, Keith L.; Carpenter, Anne E.; Alexander, Brian M.; Agar, Nathalie Y.R.; Rodig, Scott J.; Bradshaw, Elizabeth M.; Santagata, Sandro

doi:10.18632/oncotarget.3082

Cited by 140 publications

(141 citation statements)

References 49 publications

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“…Other cytogenetic alterations and specific gene mutations have been identified in patients with AAM that differ from those found in WHO grade I meningiomas [35]. Other molecular analyses have found that AAM cells express PD-L1, a checkpoint molecule capable of suppressing an effective immune response, potentially providing an immunosuppressive microenvironment and making immunotherapy an alternative therapy for these type of aggressive tumors [36]. Another important gene with effects in meningioma progression is p53-regulator PPM1D [37].…”

Section: Discussionmentioning

confidence: 99%

Atypical and anaplastic meningioma: outcomes in a population based study

et al. 2017

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Atypical and anaplastic meningiomas (AAM) are aggressive tumors. This study is aimed at examining associations between patient and tumor-related factors and tumor-related death in patients with AAM. We conducted a population-based cohort study utilizing prospectively collected data from the Surveillance, Epidemiology, and End Results (SEER) database. Patients with diagnosis of AAM from 1973 to 2012 in the SEER database were included. Patients lacking clinical information were excluded. Multivariate analysis between patient and lesion characteristics, and AAM-related death was performed to adjust for confounding factors. We identified and included 522 patients in our study. Mean age at diagnosis was 60.8 ± 15.7 years. The majority of patients were White(73%), 15.5% Black, and 9.8% Asian. Average tumor size was 48.2 ± 20.3 mm. The tumor was locally confined in 57.1%, whereas it had intracranial extension in 29.3%, and extracranial extension in 8.8% of patients. The vast majority (94.8%) of tumors were supratentorial. Gross total resection (GTR) was documented in 65.5% of patients. Age at diagnosis (p = 0.001), tumor size (p = 0.003), surgery result (GTR vs. subtotal resection, p = 0.027), and radiation therapy (p = 0.2) were found to be significantly different between the comparison groups. In a multivariate proportional competing risk regression analysis age (HR 1.03, CI [1.01,1.04], p < 0.001), infratentorial location (HR 2.81, CI [1.20, 6.56], p = 0.017), tumor size (HR 1.01, CI [1.00,1.02], p = 0.032),and radiation treatment (HR 1.52, CI [1.11, 2.09], p = 0.01) were significantly associated with tumor-related death. The association of age at diagnosis, tumor size, location, and radiotherapy with overall survival in patients with AAM is demonstrated. The results provide a context for individualized treatment plans in patients with AAM. Additional studies focusing on issues such as the use of radiation and chemotherapy will clarify the best modality to achieve disease control.

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Section: Discussionmentioning

confidence: 99%

Atypical and anaplastic meningioma: outcomes in a population based study

et al. 2017

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“…Appropriate positive and negative controls were used throughout. In situ hybridization of TERT mRNA transcripts was performed using the RNAscope® assay with Probe-Hs-TERT (Cat# 605511, Advanced Cell Diagnostics, USA), following manufacturer’s protocols [10,14]. …”

Section: Methodsmentioning

confidence: 99%

“…Red indicates gain and blue indicates loss. (C) In situ hybridization of TERT mRNA transcripts using a TERT -specific RNAscope probe in FFPE sections of the meningioma samples [10,14]. (D) Immunohistochemistry for ARID1A.…”

Section: Figurementioning

confidence: 99%

“…These meningiomas are classified as World Health Organization (WHO) grade II or III and are associated with premature mortality [1]. Despite emerging understanding of the genetic changes underlying meningioma formation [2–10], the factors that drive malignant progression in meningioma remain poorly understood [11–13]. We encountered a case of a unique untreated intraventricular meningioma, which allowed us to investigate molecular factors associated with tumor progression and dedifferentiation.…”

Section: Introductionmentioning

confidence: 99%

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ARID1A and TERT promoter mutations in dedifferentiated meningioma

Abedalthagafi¹,

Bi²,

Merrill³

et al. 2015

Cancer Genetics

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While WHO grade I meningiomas are considered benign, patients with WHO grade III meningiomas have very high mortality. The principles underlying tumor progression in meningioma are largely unknown yet a detailed understanding of these mechanisms will be required for effective management of patients with these high-grade, lethal tumors. We present a case of an intraventricular meningioma that at first presentation displayed remarkable morphologic heterogeneity – comprised of distinct regions independently fulfilling histopathologic criteria for WHO grade I, II and III designations. The lowest-grade regions had classic meningothelial features while the highest grade regions were markedly dedifferentiated. While progression in meningiomas is generally observed during recurrence following radiation and systemic medical therapies the current case offers us a snapshot into histologic progression and intratumor heterogeneity in a native, pre-treatment context. Using whole exome sequencing (WES) and high resolution array comparative genomic hybridization (aCGH) we observe marked genetic heterogeneity between the various areas. Notably, in the higher grade regions we find increased aneuploidy with progressive loss of heterozygosity, the emergence of mutations in the TERT promoter and compromise of ARID1A. These findings provide new insights into intratumoral heterogeneity in the evolution of malignant phenotypes in anaplastic meningiomas and potential pathways of malignant progression.

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“…Gene expression studies and cell line models further suggest activation of MAPK, Notch, and growth factor autocrine loops in meningiomas. 23,[40][41][42]58 Aside from mechanisms that promote 27 Greater insight into recurrent drivers underlying malignant transformation may be acquired through future genomic studies.…”

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confidence: 99%

Genomic landscape of intracranial meningiomas

Abedalthagafi

Horowitz

et al. 2016

JNS

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M eningioMas are the most common primary intracranial neoplasms in adults, accounting for 35.8% of all primary CNS tumors and more than 53% of all benign CNS tumors diagnosed in the US. 65 Autopsy and imaging studies suggest an even higher prevalence, affecting almost 3% of women.98 These lesions are believed to arise from progenitor cells that give rise to both the arachnoid cap cells of the arachnoid layer and fibroblasts that reside in the inner dura mater. 18,45The vast majority of meningiomas are indolent.36 A small percentage, however, display malignant behavior characterized by invasive growth patterns and/or markedly higher recurrence rates. Notably, even meningiomas that lack histological features of malignancy recur at significant rates. Multimodality therapy including surgery and radiation is often used in the management of these subsets of meningioma, but other therapeutic modalities have failed to improve control rates. Aggressive meningiomas and the meningiomatosis that occur in hereditary syndromes remain difficult clinical problems. Although most meningiomas are "benign," there is substantial morbidity associated with recurrence, and clinical management remains challenging for clinicians worldwide.Unbiased genome-and exome-wide sequencing approaches have implicated a central core of gene mutations that are associated with a substantial percentage of these tumors. This information may highlight therapeutic targets and enhance biological classification of meningioma. 12,22 Just as an improved understanding of genomic alterations has changed the way we classify and treat cancers including chronic myelogenous leukemia, melanoma, and lung cancer, similar interrogation of the meningioma genome has revealed potential novel treatment pathways for patients harboring these tumors. Meningiomas are the most common primary intracranial neoplasms in adults. Current histopathological grading schemes do not consistently predict their natural history. Classic cytogenetic studies have disclosed a progressive course of chromosomal aberrations, especially in high-grade meningiomas. Furthermore, the recent application of unbiased nextgeneration sequencing approaches has implicated several novel genes whose mutations underlie a substantial percentage of meningiomas. These insights may serve to craft a molecular taxonomy for meningiomas and highlight putative therapeutic targets in a new era of rational biology-informed precision medicine.

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Increased expression of the immune modulatory molecule PD-L1 (CD274) in anaplastic meningioma

Cited by 140 publications

References 49 publications

Atypical and anaplastic meningioma: outcomes in a population based study

Atypical and anaplastic meningioma: outcomes in a population based study

ARID1A and TERT promoter mutations in dedifferentiated meningioma

Genomic landscape of intracranial meningiomas

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