Angiocentric Glioma Research Articles

MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes

Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection.

Extra-temporal pediatric low-grade gliomas and epilepsy.

Low-grade gliomas, especially glioneuronal tumors, are a common cause of epilepsy in children. Seizures associated with low-grade pediatric tumors are medically refractory and present a significant burden to patients. Often, morbidity and patients´ quality of life are determined rather by the control of seizures than the oncological process itself and the resolution of epilepsy represents an important part in the treatment of LGGs. The pathogenesis of tumor-related seizures in focal LGG tumors is multifactorial, and mechanisms differ probably among patients and tumor types. Pediatric low-grade tumors associated with epilepsy include a series of neoplasms that have a pure astrocytic or glioneuronal lineage. They are usually benign tumors with a neocortical localization typically in the temporal lobes, but also in other supratentorial locations. Gangliogliomas and dysembryoplastic neuroepithelial tumors (DNET) are the most common entities together with astrocytic gliomas (pilocytic astrocytomas and pleomorphic xanthoastrocytoma) and angiocentric gliomas, and dual pathology is found in up to 40% of glioneuronal tumors. The treatment of low-grade gliomas and associated epilepsy is based mainly on resection and the extent of surgery is the main predictor of postoperative seizure control in patients with a LGG. Long-term epilepsy-associated tumors (LEATs) tend to be well-circumscribed, and therefore, the chances for a complete resection and epilepsy control with a safe approach are very high. New treatments have emerged as alternatives to open microsurgical approaches, including laser thermal ablation or the use of BRAF inhibitors. Future advances in identifying seizure-related biomarkers and molecular tumor pathways will facilitate targeted treatment strategies that will have a deep impact both in oncologic and epilepsy outcomes.

Cortically-based Brain Tumors in Children: A Decision-tree Approach in the Radiology Reading Room.

Cortically-based brain tumors in children constitute a unique set of tumors with variably aggressive biological behavior. As radiologists play an integral role on the multidisciplinary medical team, a clinically useful and easy-to-follow flowchart for the differential diagnoses of these complex brain tumors is essential.This proposed algorithm tree provides the latest insights into the typical imaging characteristics and epidemiologic data that differentiate the tumor entities, taking into perspective the 2021 World Health Organization's classification and highlighting classic as well as newly identified pathologic subtypes using current molecular understanding.ABBREVIATIONS: Astroblastoma=AB) Angiocentric glioma (AG) Atypical teratoid rhabdoid tumor (ATRT) Central Nervous System tumor (CNS) CNS neuroblastoma FOXR2-activated (NB-FOXR2) Desmoplastic infantile glioma/astrocytoma (DIG/DIA) Diffuse hemispheric glioma, H3 G34-mutant (DHG) Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) Dysembryoplastic neuroepithelial tumor (DNET) Embryonal Tumors with Multilayered Rosettes (ETMR) Ependymoma (EP) Focal cortical dysplasia (FCD) Ganglioglioma/gangliocytoma (GG) Infant-type hemispheric glioma (IHG) Intracranial pressure (ICP) Long-term epilepsy-associated tumors (LEATs) Pediatric diffuse low-grade gliomas (pLGG) MR spectroscopy (MRS) Multinodular and vacuolating neuronal tumor (MVNT) Overall survival (OS) Pediatric diffuse high-grade gliomas (pHGG).

Clinical characteristics and detection of MYB-QKI fusions in patients with angiocentric glioma.

Angiocentric glioma (AG), a benign tumor identified within the last two decades, was officially included in the 2007 WHO Classification of Tumors of the Central Nervous System, WHO grade I. The tumor is relatively rare, with only approximately 100 cases reported. We aim to complement the characteristics and long-term prognosis of AG, as well as to detect MYB-QKI fusions. The characteristics of all cases collected between 1 March 2009 and 1 March 2023 at the Beijing Sanbo Brain Hospital, Capital Medical University, were summarized and analyzed. Additionally, all fourteen patients were tested for MYB-QKI fusions. AG more predominantly occurs in adolescents (median age 16.5-year-old), and commonly presents with drug-resistant epilepsy. AG is frequently localized in the supratentorial regions and only one patient is in the brainstem. Brain parenchyma atrophy, and stalk-like signs can observe in imaging. Pathologically, tumor cells are perivascular pseudorosettes, presenting immunoreactivity for GFAP, S-100, Vimentin, "dot-like" staining for EMA, and low proliferative activity. Focal cortex dysplasia was observed in four patients. Twelve of fourteen (85.7%) patients were found with MYB-QKI fusions. Completely surgical resection typically has a satisfactory prognosis with long-term follow-up. AG is a rare benign tumor with a favorable prognosis after complete resection, characterized by refractory epilepsy, frequently occurring in adolescents. MYB-QKI fusions were detected in most AG patients, as a good defining genetic alteration pathologically. The potential presence of focal cortical dysplasia (FCD) may affect the prognosis of epilepsy.

Left-Parietal Angiocentric Glioma: Our Experience and a Review of the Literature

Background: Angiocentric glioma (AG) is a rare, benign, and slow-growing tumor. First described in 2005, it is now gaining attention with respect to the possibility of being diagnosed. Even with no statistical differences between sex, it has been reported both in children and the elderly. A total of 120 cases have been described in the literature. The aim of this study is to provide new data for a new statistical assessment of the prevalence and incidence of AG in populations. Case report: An 8-year-old male patient with no history of epilepsy and no need for antiepileptic therapy underwent surgery for a left-parietal brain lesion, revealed through MRI. Imaging was acquired after his first absence episode. The lesion was completely resected. Histological findings indicated angiocentric glioma. No signs of recurrency after two years of follow-up. Conclusion: AG is usually an epilepsy-related low-grade glioma. Few cases exhibit disease progression and exitus. Surgical management should aim for a gross total resection to avoid recurrence and persisting epilepsy. Surgery represents the gold standard in diagnosis and treatment and must be performed as soon as possible in consideration of its healing properties and its useful diagnosis.

Low-grade glioma of the temporal lobe and tumor-related epilepsy in children.

Low-grade glioma is the most common brain tumor among children and adolescents. When these tumors arise in the temporal lobe, patients frequently present with seizures that are poorly controlled with antiepileptic drugs. Here we summarize the clinical features, pathophysiology, preoperative evaluation, surgical treatment, and outcomes of pediatric patients with low-grade gliomas in the temporal lobe. We reviewed the literature on pediatric low-grade gliomas in the temporal lobe, focusing on cohort studies and systematic reviews that described surgical treatment strategies and reported both oncologic and epilepsy outcomes. The differential diagnoses of pediatric low-grade gliomas in the temporal lobe include ganglioglioma, dysembryoplastic neuroepithelial tumor, desmoplastic infantile ganglioglioma, papillary glioneuronal tumor, pilocytic astrocytoma, pleomorphic xanthoastrocytoma, angiocentric glioma, and polymorphous low-grade neuroepithelial tumor of the young. There is no consensus on the optimal surgical approach for these tumors: lesionectomy alone, or extended lesionectomy with anterior temporal lobectomy, with or without removal of mesial temporal structures. Gross total resection and shorter preoperative duration of epilepsy are strongly associated with favorable seizure outcomes, defined as Engel Class I or Class II, approaching 90% in most series. The risk of surgical complications ranges from 4 to 17%, outweighing the lifetime risks of medically refractory epilepsy. Pediatric patients with temporal low-grade glioma and tumor-related epilepsy are best managed by a multidisciplinary epilepsy surgery team. Early and appropriate surgery leads to prolonged survival and a greater likelihood of seizure freedom, improving their overall quality of life.

T2-FLAIR Mismatch: An Imaging Biomarker for Children's MYB/MYBL1-Altered Diffuse Astrocytoma or Angiocentric Glioma.

T2-FLAIR mismatch is a highly specific imaging biomarker of IDH-mutant diffuse astrocytoma in adults. It has however also been described in MYB/MYBL1-altered low grade tumors. Our aim was to assess the diagnostic power of the T2-FLAIR mismatch in IDH-mutant astrocytoma and MYB/MYBL1-altered low-grade tumors in children and correlate this mismatch with histology. We evaluated MR imaging examinations of all pediatric patients, performed at the Princess Máxima Center for Pediatric Oncology and the University Medical Center Utrecht between January 2012 and January 2023, with the histomolecular diagnosis of IDH-mutant astrocytoma, diffuse astrocytoma MYB/MYBL1-altered, or angiocentric glioma, and the presence of T2-FLAIR mismatch was assessed. Histologically, the presence of microcysts in the tumor (a phenomenon suggested to be correlated with T2-FLAIR mismatch in IDH-mutant astrocytomas in adults) was evaluated. Nineteen pediatric patients were diagnosed with either IDH-mutant astrocytoma (n = 8) or MYB/MYBL1-altered tumor (n = 11: diffuse astrocytoma, MYB- or MYBL1-altered n = 8; or angiocentric glioma n = 3). T2-FLAIR mismatch was present in 11 patients, 3 (38%) in the IDH-mutant group and 8 (73%) in the MYB/MYBL1 group. No correlation was found between T2-FLAIR mismatch and the presence of microcysts or an enlarged intercellular space in either IDH-mutant astrocytoma (P = .38 and P = .56, respectively) or MYB/MYBL1-altered tumors (P = .36 and P = .90, respectively). In our pediatric population, T2-FLAIR mismatch was more often found in MYB/MYBL1-altered tumors than in IDH-mutant astrocytomas. In contrast to what has been reported for IDH-mutant astrocytomas in adults, no correlation was found with microcystic changes in the tumor tissue. This finding challenges the hypothesis that such microcystic changes and/or enlarged intercellular spaces in the tissue of these tumors are an important part of explaining the occurrence of the T2-FLAIR mismatch.

Clinicopathological analysis of BRAF and non-BRAF MAPK pathway-altered gliomas in paediatric and adult patients: a single-institution study of 40 patients

AimsMitogen-activated protein kinase (MAPK) pathway alteration is a major oncogenic driver in paediatric low-grade gliomas (LGG) and some adult gliomas, encompassing BRAF (most common) and non-BRAF alterations. The aim was...

Long-term epilepsy associated-tumors (LEATs): what is new?

Long-term epilepsy-associated tumors (LEATs) include a series of neoplasms that commonly occur in children, adolescents, or young adults, have an astrocytic or glioneuronal lineage, are histologically benign (WHO grade1) with a neocortical localization predominantly situated in the temporal lobes. Clinically, chronic refractory epilepsy is usually the unique symptom. Gangliogliomas (GG) and dysembryoplastic neuroepithelial tumors (DNT) are the most common representative entities besides pilocytic astrocytomas (PA) and angiocentric gliomas (AG). Recent molecular studies have defined new clinicopathological entities, which are recognized by the WHO 2021 classification of brain tumors. Some of them such as diffuse astrocytoma MIB or MYBL1 altered, polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and multilocular and vacuolating neuronal tumor (MVNT) are currently considered LEATs. The relationship between LEATs and epilepsy is still a matter of debate, and there is a general agreement about the beneficial effects of an early neurosurgical intervention on the clinical outcome.

Leat-associated seizures the possible role of EAAT2, pyruvate carboxylase and glutamine synthetase

BackgroundDrug-resistant epilepsy is a common condition in patients with brain neoplasms. The pathogenesis of tumor-associated seizures is poorly understood. Among the possible pathogenetic mechanisms, the increase in glutamate concentration has been proposed. Glutamate transporters, glutamine synthetase and pyruvate carboxylase are involved in maintaining the physiological concentration of glutamate in the intersynaptic spaces. In our previous research on angiocentric gliomas, we demonstrated that all tumors lacked the expression of the main glutamate transporter EAAT2, while the expression of glutamine synthetase and pyruvate carboxylase was mostly preserved. MethodsIn the present study, we evaluated the immunohistochemical expression of EAAT2, glutamine synthetase and pyruvate carboxylase in a heterogeneous series of 25 long-term epilepsy-associated tumors (10 dysembryoplastic neuroepithelial tumors, 7 gangliogliomas, 3 subependymal giant cell astrocytomas, 3 rosette forming glioneuronal tumors, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). In order to evaluate the incidence of variants in the SLC1A2 gene, encoding EAAT2, in a large number of central nervous system tumors we also queried the PedcBioPortal. ResultsEAAT2 protein expression was lost in 9 tumors (36 %: 3 dysembryoplastic neuroepithelial tumors, 1 ganglioglioma, 3 subependymal giant cell astrocytomas, 1 diffuse astrocytoma MYB- or MYBL1-altered and 1 angiocentric glioma). Glutamine synthetase protein expression was completely lost in 2 tumors (8 %; 1 ganglioglioma and 1 diffuse astrocytoma MYB- or MYBL1-altered). All tumors of our series but rosette forming glioneuronal tumors (in which neurocytic cells were negative) were diffusely positive for pyruvate carboxylase. Consultation of the PedcBioPortal revealed that of 2307 pediatric brain tumors of different histotype and grade, 20 (< 1%) had variants in the SLC1A2 gene. Among the SLC1A2-mutated tumors, there were no angiocentric gliomas or other LEATs ConclusionsIn conclusion, unlike angiocentric gliomas where the EAAT2 loss is typical and constant, the current study shows the loss of EAAT2 expression only in a fraction of the LEATs. In these cases, we may hypothesize some possible epileptogenic role of the EAAT2 loss. The retained expression of pyruvate carboxylase may contribute to determining a pathological glutamate excess unopposed by glutamine synthetase that resulted expressed to a variable extent in the majority of the tumors. Furthermore, we can assume that the EAAT2 loss in brain tumors in general and in LEATs in particular is more conceivably epigenetic.

Review on neuroimaging in pediatric-type diffuse low-grade gliomas.

The fifth edition of the World Health Organization Classification of Tumors of the Central Nervous System (WHO CNS5) has identified a new classification system for tumors of the brain and spinal cord, highlighting the pivotal role of molecular diagnosis in accurately categorizing neoplasms. In addition to previous classifications, one of the key distinctions lies in categorizing pediatric-type diffuse low-grade gliomas (pDLGGs) and pediatric-type diffuse high-grade gliomas (pDHGGs) as distinct tumor types. Although similar in histology and morphology, pediatric diffuse gliomas are completely different from the adult type with respect to the molecular genetic characteristics, prognosis, and treatment strategies. pDLGG includes four tumor types, namely, diffuse astrocytoma, MYB- or MYBL1-altered; angiocentric glioma; polymorphous low-grade neuroepithelial tumor of the young (PLNTY); and diffuse low-grade glioma, MAPK pathway-altered, three types of which are newly recognized tumor types. Herein, we review the clinical characteristics, histopathological and molecular genetic characteristics, neuroimaging features, and prognosis of pDLGG and summarize the neuroimaging key points in diagnosing different tumor types. This review aims to evaluate and update the relevant pDLGG features and advances in neuroimaging that may assist in differential diagnosis, surgery planning, and prognostic determination of these tumor types and provide accurate diagnostic information for clinical colleagues.

JS01.3.A EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS

Abstract BACKGROUND Angiocentric glioma mainly occurs in children and young adults. It is associated with a good prognosis (CNS WHO grade 1). Molecularly, most angiocentric gliomas have a MYB-QKI fusion. Histologically, angiocentric gliomas were initially defined by angiocentric growth of the tumor cells. However, we noticed that epigenetically defined angiocentric gliomas often get different diagnoses based on their histology as they may lack this angiocentric growth pattern. We therefore wanted to further analyze epigenetically defined angiocentric gliomas and evaluate how reliable these gliomas are histologically diagnosed based on the criteria defined by the WHO. MATERIAL AND METHODS We collected 48 epigenetically defined angiocentric gliomas (37 supratentorial, 11 infratentorial) from 46 patients with sufficient tissue for histological and molecular analyses (DNA methylation analyses; RNA sequencing of a subset). The classification was done using unsupervised hierarchical cluster analyses from DNA methylation data and the brain tumor classifiers v11b4 and v12.5 (www.molecularneuropathology.org). RESULTS Angiocentric gliomas were epigenetically distinct from other gliomas including the diffuse astrocytomas, MYB- or MYBL1-altered. A MYB-QKI fusion was detected in 69% (n = 18/26) of angiocentric gliomas, confirming the diagnosis. Other fusions detected were fusions of MYB with intergenic sites, mainly close to QKI (19%; n = 5/26), and MYBL1-QKI (8%; n = 2/26). Histological workup revealed that 75% of the cases included in this study showed the typical angiocentric growth pattern. However, in many of these tumors this was not very pronounced. Many angiocentric gliomas displayed an unspecific growth pattern or resembled pilocytic astrocytoma or ependymoma. Hence, about 59% of angiocentric gliomas were initially misdiagnosed without molecular analyses (supratentorial 50%, infratentorial 100%). We obtained similar results expanding the cohort with further epigenetically defined angiocentric gliomas for which no tissue for a histological re-evaluation was available (total 68 cases; 50 supratentorial, 12 infratentorial; 65 patients). In this expanded cohort, 54% of cases were initially misdiagnosed (45% of supratentorial and 100% of infratentorial cases). CONCLUSION In summary, we show that angiocentric glioma often does not show the typical angiocentric growth pattern, resulting in different diagnoses in more than 50% of the cases without molecular analyses. Thus, DNA methylation analyses are needed for a reliable diagnosis of this tumor type.

T2-FLAIR Mismatch Sign in Pediatric Low-Grade Glioma.

No qualitative imaging feature currently predicts molecular alterations of pediatric low-grade gliomas with high sensitivity or specificity. The T2-FLAIR mismatch sign predicts IDH-mutated 1p19q noncodeleted adult gliomas with high specificity. We aimed to assess the significance of the T2-FLAIR mismatch sign in pediatric low-grade gliomas. Pretreatment MR images acquired between January 2001 and August 2018 in pediatric patients with pediatric low-grade gliomas were retrospectively identified. Inclusion criteria were the following: 1) 0-18 years of age, 2) availability of molecular information in histopathologically confirmed cases, and 3) availability of preoperative brain MR imaging with non-motion-degraded T2-weighted and FLAIR sequences. Spinal cord tumors were excluded. Three hundred forty-nine patients were included (187 boys; mean age, 8.7 [SD, 4.8] years; range, 0.5-17.7 years). KIAA1549-B-Raf proto-oncogene (BRAF) fusion and BRAF p.V600E mutation were the most common molecular markers (n = 148, 42%, and n = 73, 20.7%, respectively). The T2-FLAIR mismatch sign was present in 25 patients (7.2%). Of these, 9 were dysembryoplastic neuroepithelial tumors; 8, low-grade astrocytomas; 5, diffuse astrocytomas; 1, a pilocytic astrocytoma; 1, a glioneuronal tumor; and 1, an angiocentric glioma. None of the 25 T2-FLAIR mismatch pediatric low-grade gliomas were BRAF p.V600E-mutated. Fourteen of 25 pediatric low-grade gliomas with the T2-FLAIR mismatch sign had rare molecular alterations, while the molecular subtype was unknown for 11 tumors. The T2-FLAIR mismatch sign was not observed in the common molecular alterations, BRAF p.V600E-mutated and KIAA1549-BRAF fused pediatric low-grade gliomas, while it was encountered in pediatric low-grade gliomas with rare pediatric molecular alterations.

LGG-17. EPIGENETICALLY DEFINED ANGIOCENTRIC GLIOMAS MAY LACK ANGIOCENTRIC GROWTH AND INSTEAD SHOW A VARIETY OF GROWTH PATTERNS

Abstract Angiocentric glioma mainly occurs in children and young adults. It is associated with a good prognosis (CNS WHO grade 1). Molecularly, most angiocentric gliomas have a MYB-QKI fusion. Histologically, angiocentric gliomas were initially defined by an angiocentric growth of the tumor cells. However, we noticed that epigenetically defined angiocentric gliomas often get different diagnoses based on their histology as they may lack this angiocentric growth pattern. We collected 48 epigenetically defined angiocentric gliomas from 46 patients with sufficient tissue for histological and molecular analyses (DNA methylation analyses; RNA sequencing of a subset; 37 supratentorial and 11 infratentorial cases). The classification was done using unsupervised hierarchical cluster analyses from DNA methylation data and the brain tumor classifiers v11b4 and v12.5 (www.molecularneuropathology.org). Angiocentric gliomas were epigenetically distinct from the diffuse astrocytomas, MYB- or MYBL1-altered. A MYB-QKI fusion was detected in 69% (n = 18/26) of angiocentric gliomas, confirming the diagnosis. Other fusions detected were fusions of MYB with intergenic sites, mainly close to QKI (19%; n = 5/26), and MYBL1-QKI (8%; n = 2/26). We then did a histological workup of these cases. Only 75% showed the typical angiocentric growth pattern that often was not very pronounced. Many angiocentric gliomas displayed an unspecific growth while others resembled pilocytic astrocytoma or ependymoma. Hence, about 59% of angiocentric gliomas were initially misdiagnosed without molecular analyses (supratentorial 50%, infratentorial 100%). We obtained similar results expanding the cohort with further epigenetically defined angiocentric gliomas for which no tissue for a histological re-evaluation was available (total 68 cases; 50 supratentorial, 12 infratentorial; 65 patients). In this expanded cohort, 54% of cases were initially misdiagnosed (45% of supratentorial and 100% of infratentorial cases). In summary, we show that angiocentric glioma often does not show the typical angiocentric growth pattern. Thus, molecular analyses are needed for a reliable diagnosis.

Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome.

The WHO 2021 classification of central nervous system cancers distinguishes diffuse gliomas that arise in adults (referred to as the "adult type") and those that arise in children (defined as "paediatric") based on clinical and molecular characteristics."). However, paediatric-type gliomas may occasionally be present in younger adults and occasionally adult-type gliomas may occur in children. Diffuse low-grade paediatric glioma includes diffuse astrocytoma altered by MYB or MYBL1, low-grade polymorphic juvenile neuroepithelial tumour, angiocentric glioma, and diffuse low-grade glioma with an altered MAPK pathway. Here, we examine these newly recognised entities according to WHO diagnostic criteria and propose an integrated diagnostic approach that can be used to separate these clinically and biologically distinct tumor groups.

MODL-38. DEVELOPMENTAL EFFECTS OF MYBL1 ACTIVATION ON MURINE BRAIN AND GLIAL DEVELOPMENT

Abstract Low-grade gliomas (LGG) represent 30% of pediatric brain tumors. Their cellular origins are unknown but are presumed to arise from subtle alterations of progenitor cell cycle regulation during brain development. Rearrangements activating MYB and MYBL1 have been identified as drivers of LGG in angiocentric glioma and diffuse astrocytomas, respectively, but the roles of these genes in the normal brain and the development of LGG are poorly understood. We first performed a developmental analysis of human and mouse Mybl1 expression from bulk and single-cell RNA-sequencing and identified exclusive expression of MYBL1 in neural stem and progenitor cells in the ganglionic eminence. We also found that MYBL1high cell transcriptomes are enriched in genes functionally involved in centromere and mitotic processes, strongly suggesting an association between MYBL1 expression and cellular proliferation states. We next hypothesized that C-terminal truncation may drive tumorigenesis through a direct increase in MYBL1 expression and cell proliferation. We developed a novel Cre-dependent knock-in mouse-model for human truncated MYBL1 expression and tested effects in oligodendroglial(Olig2-cre), astrocytic hGFAP-cre), and somatic(Ubiquitin-cre) cell types. In Ubq-cre:R26-MYBL1-tr mice there was expression and dysplasia in the salivary gland but no significant effects on brain development. In Olig2-Cre+/tg:R26-MYBL1-tr+/fl mice we observed higher susceptibility to motor seizures, early postnatal death without gross or microscopic abnormalities of brain morphology. In contrast, expression in stem cells and astrocytes of hGFAP-Cre+/tg:R26-MYBL1-tr+/flmice drove dramatic abnormalities in brain development and altered proliferation of progenitor and stem cells, but not glioma formation. Single-cell RNA sequencing of MYBL1-tr cells from mNSCs and brains of mice were also used to determine patterns of altered expression driven by MYBL1-tr. These results indicate that aberrant MYBL1 activation affects neural stem/progenitor cell and brain development through altered cell proliferation. Future targeting of the pathways identified may be therapeutically beneficial for patients with LGG driven by MYB-family oncogenes.

The landscape of common genetic drivers and DNA methylation in low-grade (epilepsy-associated) neuroepithelial tumors: A review.

Low-grade neuroepithelial tumors (LNETs) represent an important group of central nervous system neoplasms, some of which may be associated to epilepsy. The concept of long-term epilepsy-associated tumors (LEATs) includes a heterogenous group of low-grade, cortically based tumors, associated to drug-resistant epilepsy, often requiring surgical treatment. LEATs entities can sometimes be poorly discriminated by histological features, precluding a confident classification in the absence of additional diagnostic tools. This study aimed to provide an updated review on the genomic findings and DNA methylation profiling advances in LNETs, including histological entities of LEATs. A comprehensive search strategy was conducted on PubMed, Embase, and Web of Science Core Collection. High-quality peer-reviewed original manuscripts and review articles with full-text in English, published between 2003 and 2022, were included. Results were screened based on titles and abstracts to determine suitability for inclusion, and when addressed the topic of the review was screened by full-text reading. Data extraction was performed through a qualitative content analysis approach. Most LNETs appear to be driven mainly by a single genomic abnormality and respective affected signaling pathway, including BRAF p.V600E mutations in ganglioglioma, FGFR1 abnormalities in dysembryoplastic neuroepithelial tumor, MYB alterations in angiocentric glioma, BRAF fusions in pilocytic astrocytoma, PRKCA fusions in papillary glioneuronal tumor, between others. However, these molecular alterations are not exclusive, with some overlap amongst different tumor histologies. Also, clustering analysis of DNA methylation profiles allowed the identification of biologically similar molecular groups that sometimes transcend conventional histopathological classification. The exciting developments on the molecular basis of these tumors reinforce the importance of an integrative histopathological and (epi)genetic classification, which can be translated into precision medicine approaches.

LGG-45. Genetic dependencies inMYB/MYBL1-driven pediatric low-grade glioma models

AIM: Pediatric low-grade gliomas (pLGGs) are a heterogenous group of tumors, diverse in their localization, histology, mutational landscape, clinical behavior, and treatment response. Genomic alterations impacting the MYB family of transcription factors were identified in two distinct pLGG subtypes: Angiocentric Gliomas (AG) and Diffuse Astrocytomas (DA). The molecular profiles and therapeutic vulnerabilities associated with these genomic alterations remain unexplored. In this study we highlight the use of genome-wide CRISPR/Cas9 knock-out screens for an unbiased identification of translatable therapeutic targets. METHODOLOGY: Given the lack of patient-derived pLGG cell lines, we engineered in vitro pLGG mouse and human neural stem cell (NSC) models to harbor pLGG-relevant genomic alterations. We performed single cell RNA sequencing to investigate the transcriptional profiles driven by these mutations and to dissect the central regulatory networks enabling tumorigenesis. Specific genetic dependencies associated with MYB/MYBL1 mutations were screened using the Brie genome-wide mouse CRISPR lentiviral knock-out pooled library, consisting of 78,637 single guide RNAs (sgRNAs) targeting 19,674 mouse genes. RESULTS: We have successfully generated in vitro NSC-based pLGG models crucial to deepening our knowledge on pLGG biology and the identification of translatable therapeutic targets. Genome-scale CRISPR/Cas9 knock-out screens in isogenic NSCs models, expressing distinct MYB/MYBL1 alterations or a control transgene, revealed several differential genetic dependencies. Among the top identified dependencies are regulators of cell-stress response, cell-cycle progression, and modulators of the ubiquitin-proteasome degradation pathway. CONCLUSION: Genome-wide CRISPR knock-out screens are a powerful tool for the unbiased identification of mutation-specific genetic dependencies that can be explored as candidates for precision medicine approaches.

Pediatric-type diffuse low grade gliomas: Histomolecular profile and practical approach to their integrated diagnosis according to the WHO CNS5 classification.

Low-grade gliomas are the most common primary central nervous system (CNS) neoplasms in the pediatric age group. The majority of these tumors are circumscribed, while diffuse low-grade gliomas are relatively rare. The pediatric type diffuse low-grade gliomas (pDLGG) have a distinctly different biological behavior, molecular profile, and clinical outcome as compared to their adult counterpart. In the 5th edition of World Health Organization (WHO) CNS classification, pDLGGs are subclassified into four distinct histomolecular entities, namely, (i) diffuse astrocytoma, MYB- or MYBL1-altered, (ii) angiocentric glioma, (iii) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and (iv) diffuse low-grade glioma, MAPK pathway-altered. Although the molecular profile, to a great extent, aligns with the morphological features, it is not specific. Many of the molecular alterations described in pDLGG have therapeutic implications with the availability of newer targeted therapies. A wide range of testing platforms are available for routine assessment of these molecular alterations in clinical laboratories, though WHO does not recommend any particular method.

Neuroimaging features of angiocentric glioma: A case series and systematic review.

Background and PurposeAngiocentric gliomas (AGs) are epileptogenic low‐grade gliomas in young patients. We aimed to investigate the MRI findings of AGs and systematically review previous publications and three new cases.MethodsWe searched PubMed, Elsevier's abstract and citation database, and Embase databases and included 50 patients with pathologically proven AGs with analyzable preoperative MRI including 3 patients from our institution and 47 patients from 38 publications (median age, 13 years [range, 2‐83 years]; 35 men). Two board‐certified radiologists reviewed all images. The relationships between seizure/epilepsy history and MRI findings were statistically analyzed. Moreover, clinical and imaging differences were evaluated between supratentorial and brainstem AGs.ResultsIntratumoral T1‐weighted high‐intensity areas, stalk‐like signs, and regional brain parenchymal atrophy were observed in 23 out of 50 (46.0%), 10 out of 50 (20.0%), and 14 out of 50 (28.0%) patients, respectively. Intratumoral T1‐weighted high‐intensity areas were observed significantly more frequently in patients with stalk‐like signs (positive, 9/10 vs. negative, 14/40, p = .0031) and regional atrophy (13/14 vs. 10/36, p = .0001). There were significant relationships between the length of seizure/epilepsy history and presence of intratumoral T1‐weighted high‐intensity area (median 3 years vs. 0.5 years, p = .0021), stalk‐like sign (13.5 vs. 1 year, p < .0001), and regional atrophy (14 vs. 0.5 years, p < .0001). Patients with brainstem AGs (n = 7) did not have a seizure/epilepsy history and were significantly younger than those with supratentorial AGs (median, 5 vs. 13 years, p < .0001, respectively).ConclusionsIntratumoral T1‐weighted high‐intensity areas, stalk‐like signs, and regional brain atrophy were frequent imaging features in AG. We also found that affected age was different between supratentorial and brainstem AGs.