Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial (original) (raw)
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Genetic signature and treatment of pediatric high‑grade glioma
Molecular and Clinical Oncology, 2021
Pediatric high-grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0-32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild-type patients at 20 months was 68% [confidence interval (CI): 38-85%] compared with 28% (CI: 0.4-60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild-type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low-grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma.
Clinical Cancer Research, 2020
Purpose: The HERBY trial evaluated the benefit of the addition of the antiangiogenic agent Bevacizumab (BEV) to radiotherapy/temozolomide (RT/TMZ) in pediatric patients with newly diagnosed non-brainstem high-grade glioma (HGG). The work presented here aims to correlate imaging characteristics and outcome measures with pathologic and molecular data. Experimental Design: Radiological, pathologic, and molecular data were correlated with trial clinical information to retrospectively re-evaluate event-free survival (EFS) and overall survival (OS). Results: One-hundred thirteen patients were randomized to the RT/TMZ arm (n = 54) or the RT/TMZ+BEV (BEV arm; n = 59). The tumor arose in the cerebral hemispheres in 68 patients (Cerebral group) and a midline location in 45 cases (Midline group). Pathologic diagnosis was available in all cases and molecular data in 86 of 113. H3 K27M histone mutations were present in 23 of 32 Midline cases and H3 G34R/V mutations in 7 of 54 Cerebral cases. Tot...
The genetic signatures of pediatric high-grade glioma: no longer a one-act play
Seminars in radiation oncology, 2014
Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pHGG and adult HGG and have uncovered unique molecular drivers among subgroups within pHGG. The 3 core adult HGG pathways, the receptor tyrosine kinase-Ras-phosphatidylinositide 3-kinase, p53, and retinoblastoma networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric nonbrainstem (pNBS)-HGG. In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared with pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular differ...
Molecular Landscape in Infant High-Grade Gliomas: A Single Center Experience
Diagnostics, 2022
High-grade gliomas (HGG) represent about 15% of all pediatric brain tumors, with a dismal prognosis and survival rates ranging from 15 to 35%. Approximately 10–12% of pediatric HGGs (pHGG) occur in children younger than five years of age at diagnosis, specifically infants (iHGG), with an unexpected overall survival rate (OS) in 60–70% of cases. In the literature, iHGGs include a large variety of heterogeneous lesions with different molecular profiles that likely explain their different outcomes. We report our single-institution experience of iHGG including 11 children under five years of age with newly diagnosed HGG between 2011 and 2021. All patients received surgery and adjuvant chemotherapy; only two patients received radiotherapy because their age at diagnosis was more than four years-old. Molecular investigations, including next generation sequencing (NGS) and DNA methylation, detected three NTRK-fusions, one ROS1-fusions, one MN1-rearrangement, and two PATZ1-fusions. According...
Pediatric high-grade glioma: A heterogeneous group of neoplasms with different molecular drivers
Glioma, 2018
High-grade glioma (HGG) accounts for ~11% of all central nervous system tumors in children aged 0-14 years. [1] The term designates malignant, diffuse, infiltrating astrocytic tumors of both the World Health Organization (WHO) Grade III (anaplastic astrocytoma) and Grade IV (glioblastoma multiforme) gliomas. The histological appearance is the same of adult malignant gliomas, and in the past, they were grouped with their adult counterparts. However, in contrast to adults, the prognostic/biologic relevance of histologically distinguishing between Grade III and Grade IV in children is not so evident. The gliomatosis cerebri, no more a distinct entity, is considered a clinical-radiological pattern of a diffuse glioma-infiltrating multiple brain regions. [2-5] Pediatric HGG (pHGG) is a relatively rare disease occurring in approximately one in 100,000 individuals with the same bad prognosis as those that arise in adults (median survival 12-15 months). [6] Although they can occur in the cerebral hemispheres as in adults, approximately one-half of pHGG arise in the brain stem, most frequently within the ventral pons, as diffuse intrinsic pontine glioma (DIPG), in midline structures, including the thalamus (13%) [7] and spinal cord (3%), [8] as well as the cerebellum (5%). [9] In recent years, extensive use of high-throughput molecular profiling techniques has largely increased our knowledge of the origin and biological features of these childhood neoplasms. The resulting data have led to a major reclassification of pHGG based on molecular subgrouping with significant clinical correlations in terms of age at presentation, anatomical location, and prognosis. Although DNA copy number, [10,11] gene expressions, [10,12] and even microRNA [13] profiling were known to differ in
Neuro-Oncology Practice, 2015
Background Glioblastoma (GBM) in children is rare. Pediatric GBM have a distinct molecular profile as compared to adult GBM. There are relatively few studies of pediatric GBMs and no standard of care on adjuvant therapy. We aimed to evaluate the clinical outcome and molecular profile of pediatric GBM. Methods and Materials Between 2004 and 2013, 66 consecutive children with histologically proven GBM were identified from our database. The majority of the children underwent maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolomide. Immunohistochemical staining was performed for p53, MIB-1 labeling index, MGMT overexpression, and EGFR amplification and isocitrate dehydrogenase (IDH1) R132H point mutation. Survival and impact of possible prognostic factors on outcomes were analyzed. Result Median survival was 15 months. The overall survival rate at 1 year was 62%, at 2 years was 30%, and at 3 years was 27%. Patients with thalamic tumors (P < .001...
Acta neuropathologica, 2017
Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show ...
Nature Communications, 2021
Long-term complications such as radiation-induced second malignancies occur in a subset of patients following radiation-therapy, particularly relevant in pediatric patients due to the long follow-up period in case of survival. Radiation-induced gliomas (RIGs) have been reported in patients after treatment with cranial irradiation for various primary malignancies such as acute lymphoblastic leukemia (ALL) and medulloblastoma (MB). We perform comprehensive (epi-) genetic and expression profiling of RIGs arising after cranial irradiation for MB (n = 23) and ALL (n = 9). Our study reveals a unifying molecular signature for the majority of RIGs, with recurrent PDGFRA amplification and loss of CDKN2A/B and an absence of somatic hotspot mutations in genes encoding histone 3 variants or IDH1/2, uncovering diagnostic markers and potentially actionable targets.
Pediatric high-grade glioma: biologically and clinically in need of new thinking
Neuro-oncology, 2016
High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and sugg...