Comprehensive Genomic Profiling of 282 Pediatric Low- and High-Grade Gliomas Reveals Genomic Drivers, Tumor Mutational Burden, and Hypermutation Signatures.
Johnson Adrienne,Severson Eric,Gay Laurie,Vergilio Jo-Anne,Elvin Julia,Suh James,Daniel Sugganth,Covert Mandy,Frampton Garrett M,Hsu Sigmund,Lesser Glenn J,Stogner-Underwood Kimberly,Mott Ryan T,Rush Sarah Z,Stanke Jennifer J,Dahiya Sonika,Sun James,Reddy Prasanth,Chalmers Zachary R,Erlich Rachel,Chudnovsky Yakov,Fabrizio David,Schrock Alexa B,Ali Siraj,Miller Vincent,Stephens Philip J,Ross Jeffrey,Crawford John R,Ramkissoon Shakti H
The oncologist
BACKGROUND:Pediatric brain tumors are the leading cause of death for children with cancer in the U.S. Incorporating next-generation sequencing data for both pediatric low-grade (pLGGs) and high-grade gliomas (pHGGs) can inform diagnostic, prognostic, and therapeutic decision-making. MATERIALS AND METHODS:We performed comprehensive genomic profiling on 282 pediatric gliomas (157 pHGGs, 125 pLGGs), sequencing 315 cancer-related genes and calculating the tumor mutational burden (TMB; mutations per megabase [Mb]). RESULTS:In pLGGs, we detected genomic alterations (GA) in 95.2% (119/125) of tumors. was most frequently altered (48%; 60/125), and missense (17.6%; 22/125), loss of function (8.8%; 11/125), and (5.6%; 7/125) mutations were also detected. Rearrangements were identified in 35% of pLGGs, including , , , , and fusions. Among pHGGs, GA were identified in 96.8% (152/157). The genes most frequently mutated were (49%; 77/157), (37.6%; 59/157), (24.2%; 38/157), (22.2%; 35/157), and (21.7%; 34/157). Interestingly, most mutations (81.4%; 35/43) were the variant K28M. Midline tumor analysis revealed mutations (40%; 40/100) consisted solely of the K28M variant. Pediatric high-grade gliomas harbored oncogenic , , , and fusions. Six percent (9/157) of pHGGs were hypermutated (TMB >20 mutations per Mb; range 43-581 mutations per Mb), harboring mutations deleterious for DNA repair in , and genes (78% of cases). CONCLUSION:Comprehensive genomic profiling of pediatric gliomas provides objective data that promote diagnostic accuracy and enhance clinical decision-making. Additionally, TMB could be a biomarker to identify pediatric glioblastoma (GBM) patients who may benefit from immunotherapy. IMPLICATIONS FOR PRACTICE:By providing objective data to support diagnostic, prognostic, and therapeutic decision-making, comprehensive genomic profiling is necessary for advancing care for pediatric neuro-oncology patients. This article presents the largest cohort of pediatric low- and high-grade gliomas profiled by next-generation sequencing. Reportable alterations were detected in 95% of patients, including diagnostically relevant lesions as well as novel oncogenic fusions and mutations. Additionally, tumor mutational burden (TMB) is reported, which identifies a subpopulation of hypermutated glioblastomas that harbor deleterious mutations in DNA repair genes. This provides support for TMB as a potential biomarker to identify patients who may preferentially benefit from immune checkpoint inhibitors.
10.1634/theoncologist.2017-0242
A comparative analysis of clinicopathological features and survival among early adolescents/young adults and children with low-grade glioma: a report from the Children's Oncology Group.
Margol Ashley S,Yeo Kee Kiat,Xia Caihong,Onar Arzu,Robison Nathan J,Freyer David R,Dhall Girish
Journal of neuro-oncology
BACKGROUND:For several types of cancer, biological differences and outcome disparities have been documented in adolescents/young adults (AYAs, 15-39 years old) versus children. This study compared clinicopathological features and survival between younger AYAs and children with low-grade glioma (LGG), a common brain tumor among AYAs. METHODS:This was a secondary analysis of Children's Oncology Group legacy study CCG-9891/POG-9130, which enrolled participants 0-21 years of age with newly-diagnosed LGG treated with surgery alone. For analysis, participants were categorized as children (0-14 years old) or early AYAs (eAYAs, 15-21 years old) and compared on demographics, clinical presentation, tumor characteristics, surgical outcomes, progression-free survival (PFS) and overall survival (OS). RESULTS:Among 468 children and 50 eAYAs, more eAYAs presented with seizures (34.0% vs. 19.2%; p = 0.015), without other significant differences in clinicopathological features. 5-year PFS rates for children and eAYA were 80.2% (95% confidence interval [95% CI], 76.1-83.7) and 83.0% (95% CI 68.8-91.1), respectively; 5-year OS rates were 97.3% (95% CI 95.2-98.5) and 95.4% (95% CI 82.7-98.8), respectively. Multivariable analysis including all participants showed presence of residual tumor to be an independent predictor of PFS (< 1.5 cm, hazard ratio [HR] 5.93 [95% CI 3.45-10.18]) and (≥ 1.5 cm, HR 8.38 [95% CI 4.75-14.79]) (p < 0.001), while midline-chiasmatic location (HR 9.69 [95% CI 3.05-30.75], p < 0.001) and non-pilocytic astrocytoma histology (HR 6.77 [95% CI 2.35-19.49], p < 0.001) were independent predictors of OS. CONCLUSION:Unlike several other cancers, LGG has similar presenting features and survival for both eAYAs and children. This support continuing a unified treatment approach and enrollment of eAYAs in pediatric clinical trials for LGGs.
10.1007/s11060-018-2983-5
Radiation Therapy for Optic Pathway and Hypothalamic Low-Grade Gliomas in Children.
Tsang Derek S,Murphy Erin S,Merchant Thomas E
International journal of radiation oncology, biology, physics
PURPOSE:The long-term survival of pediatric patients with optic pathway or hypothalamic low-grade glioma (LGG) who receive radiation therapy (RT) has not been previously assessed. METHODS AND MATERIALS:A retrospective study was performed of all patients with optic-hypothalamic pediatric LGG treated with RT at a single institution. Eligible patients were aged ≤21 years at the time of RT and had localized LGG diagnosed by neuroimaging or histology. The median RT dose was 54 Gy, delivered in 30 fractions. Event-free survival (EFS) was defined as survival without progression or secondary high-grade glioma. Days were counted from the first day of RT. RESULTS:Eighty-nine patients were included in the study, with a median follow-up period of 12.5 years. Of the patients, 14 had neurofibromatosis type 1 (NF-1). The 10-year EFS rate was 61.9% (95% confidence interval [CI], 31.2%-82.1%) for patients with NF-1 and 67.5% (95% CI, 54.8%-77.3%) for those without NF-1. The 10-year overall survival rate was 92.3% (95% CI, 56.6%-98.9%) for patients with NF-1 and 98.4% (95% CI, 89.1%-99.8%) for those without NF-1. Pre-RT chemotherapy (which was more commonly given to younger patients) was associated with reduced EFS, whereas younger age was associated with reduced overall survival. Possible RT-induced neoplasms developed in 8 patients, including 4 with NF-1. The 10-year cumulative incidence of clinically significant vasculopathy was 7.1% (95% CI, 2.9%-13.9%); vasculopathy did not develop in any child aged >10 years at the commencement of RT. CONCLUSIONS:RT is an effective treatment for optic-hypothalamic LGG. Older children without NF-1 have a low risk of late toxicity. RT can be considered for selected younger patients or individuals with NF-1 as a salvage treatment after progression.
10.1016/j.ijrobp.2017.07.023
PD-L1 Expression in Pediatric Low-Grade Gliomas Is Independent of BRAF V600E Mutational Status.
Journal of neuropathology and experimental neurology
To evaluate a potential relationship between BRAF V600E mutation and PD-L1 expression, we examined the expression of PD-L1 in pediatric high- and low-grade glioma cell lines as well as a cohort of pediatric low-grade glioma patient samples. Half of the tumors in our patient cohort were V600-wildtype and half were V600E mutant. All tumors expressed PD-L1. In most tumors, PD-L1 expression was low (<5%), but in some cases over 50% of cells were positive. Extent of PD-L1 expression and immune cell infiltration was independent of BRAF V600E mutational status. All cell lines evaluated, including a BRAF V600E mutant xenograft, expressed PD-L1. Transient transfection of cell lines with a plasmid expressing mutant BRAF V600E had minimal effect on PD-L1 expression. These findings suggest that the PD-1 pathway is active in subsets of pediatric low-grade glioma as a mechanism of immune evasion independent of BRAF V600E mutational status. Low-grade gliomas that are unresectable and refractory to traditional therapy are associated with significant morbidity and continue to pose a treatment challenge. PD-1 pathway inhibitors may offer an alternative treatment approach. Clinical trials will be critical in determining whether PD-L1 expression indicates likely therapeutic benefit with immune checkpoint inhibitors.
10.1093/jnen/nlz119
Pediatric low-grade gliomas: next biologically driven steps.
Neuro-oncology
Despite the fact that they are not typically life-threatening, low-grade gliomas (LGGs) remain a significant clinical challenge in pediatric neuro-oncology due to comorbidities associated with these tumors and/or their treatments, and their propensity to multiply recurs. LGGs, in total the most common brain tumors arising in childhood, can often become a chronic problem requiring decades of management. The Second International Consensus Conference on Pediatric Low-Grade Gliomas held in Padua, Italy in 2016 was convened in an attempt to advance the pace of translating biological discoveries on LGGs into meaningful clinical benefit. Topics discussed included: the implications of our growing biological understanding of the genomics underlying these tumors; the assessment of the model systems available; the implications of the molecular and histopathologic differences between adult and pediatric diffuse gliomas; and steps needed to expedite targeted therapy into late-stage clinical trials for newly diagnosed cases. Methods for the diagnostic assessment of alterations in the Ras/mitogen-activated protein kinase pathway, typical for these tumors, were also considered. While the overall tone was positive, with a consensus that progress is being and will continue to be made, the scale of the challenge presented by this complex group of tumors was also acknowledged. The conclusions and recommendations of the meeting panel are provided here as an outline of current thinking and a basis for further discussion.
10.1093/neuonc/nox141
Conventional chemotherapy and perspectives for molecular-based oncological treatment in pediatric hemispheric low-grade gliomas.
Fernández María Baro,Alonso Vanesa Pérez
Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery
INTRODUCTION:Pediatric low-grade gliomas (PLGG) are the most common primary central nervous system tumor in children. Patients in whom gross total resection can be achieved have an excellent overall (OS) and event-free survival (EFS) and do not require adjuvant therapy. However, children with unresectable tumors often experience multiple progressions and require additional treatment. CONVENTIONAL CHEMOTHERAPY:Radiotherapy results in long-term tumor control, but it is associated with significant toxicity, making chemotherapy the preferred therapeutic option. Several chemotherapy combinations have been found to be successful in PLGG, but 5-year EFS has been below 60 % with most of them. MOLECULAR-BASED TREATMENT:Recent molecular advances have led to a better understanding of the molecular pathways involved in the biology of LGG, allowing the development of promising tumor-specific, molecularly targeted therapies.
10.1007/s00381-016-3132-0
Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.
Ryall Scott,Zapotocky Michal,Fukuoka Kohei,Nobre Liana,Guerreiro Stucklin Ana,Bennett Julie,Siddaway Robert,Li Christopher,Pajovic Sanja,Arnoldo Anthony,Kowalski Paul E,Johnson Monique,Sheth Javal,Lassaletta Alvaro,Tatevossian Ruth G,Orisme Wilda,Qaddoumi Ibrahim,Surrey Lea F,Li Marilyn M,Waanders Angela J,Gilheeney Stephen,Rosenblum Marc,Bale Tejus,Tsang Derek S,Laperriere Normand,Kulkarni Abhaya,Ibrahim George M,Drake James,Dirks Peter,Taylor Michael D,Rutka James T,Laughlin Suzanne,Shroff Manohar,Shago Mary,Hazrati Lili-Naz,D'Arcy Colleen,Ramaswamy Vijay,Bartels Ute,Huang Annie,Bouffet Eric,Karajannis Matthias A,Santi Mariarita,Ellison David W,Tabori Uri,Hawkins Cynthia
Cancer cell
Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
10.1016/j.ccell.2020.03.011
Brainstem Low-Grade Gliomas in Children-Excellent Outcomes With Multimodality Therapy.
Upadhyaya Santhosh A,Koschmann Carl,Muraszko Karin,Venneti Sriram,Garton Hugh J,Hamstra Daniel A,Maher Cormac O,Betz Bryan L,Brown Noah A,Wahl Daniel,Weigelin Helmut C,DuRoss Kathleen E,Leonard Annette S,Robertson Patricia L
Journal of child neurology
Safe maximal surgical resection is the initial treatment of choice for pediatric brainstem low-grade gliomas. Optimal therapy for incompletely resected tumors or that progress after surgery is uncertain. We reviewed the clinical characteristics, therapy, and outcomes of all children with nontectal brainstem low-grade gliomas treated at the University of Michigan between 1993 and 2013. Median age at diagnosis was 6 years; histology was confirmed in 23 of 25 tumors, 64% were pilocytic astrocytoma. Nineteen patients underwent initial tumor resection; 14/19 received no upfront adjuvant therapy. Eight patients in the study had progressive disease; 5 initially resected tumors received chemotherapy at tumor relapse, all with partial or complete radiographic responses. Ten-year progression-free survival is 71% and overall survival, 100%. This single-institution retrospective study demonstrates excellent survival rates for children with brainstem low-grade gliomas. The efficacy of the well-tolerated chemotherapy in this series supports its role in the treatment of unresectable or progressive brainstem low-grade gliomas.
10.1177/0883073816675547
Response assessment in paediatric low-grade glioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.
Fangusaro Jason,Witt Olaf,Hernáiz Driever Pablo,Bag Asim K,de Blank Peter,Kadom Nadja,Kilburn Lindsay,Lober Robert M,Robison Nathan J,Fisher Michael J,Packer Roger J,Young Poussaint Tina,Papusha Ludmila,Avula Shivaram,Brandes Alba A,Bouffet Eric,Bowers Daniel,Artemov Anton,Chintagumpala Murali,Zurakowski David,van den Bent Martin,Bison Brigitte,Yeom Kristen W,Taal Walter,Warren Katherine E
The Lancet. Oncology
Paediatric low-grade gliomas (also known as pLGG) are the most common type of CNS tumours in children. In general, paediatric low-grade gliomas show clinical and biological features that are distinct from adult low-grade gliomas, and the developing paediatric brain is more susceptible to toxic late effects of the tumour and its treatment. Therefore, response assessment in children requires additional considerations compared with the adult Response Assessment in Neuro-Oncology criteria. There are no standardised response criteria in paediatric clinical trials, which makes it more difficult to compare responses across studies. The Response Assessment in Pediatric Neuro-Oncology working group, consisting of an international panel of paediatric and adult neuro-oncologists, clinicians, radiologists, radiation oncologists, and neurosurgeons, was established to address issues and unique challenges in assessing response in children with CNS tumours. We established a subcommittee to develop consensus recommendations for response assessment in paediatric low-grade gliomas. Final recommendations were based on literature review, current practice, and expert opinion of working group members. Consensus recommendations include imaging response assessments, with additional guidelines for visual functional outcomes in patients with optic pathway tumours. As with previous consensus recommendations, these recommendations will need to be validated in prospective clinical trials.
10.1016/S1470-2045(20)30064-4
Pediatric low-grade gliomas can be molecularly stratified for risk.
Yang Rui Ryan,Aibaidula Abudumijiti,Wang Wei-Wei,Chan Aden Ka-Yin,Shi Zhi-Feng,Zhang Zhen-Yu,Chan Danny Tat Ming,Poon Wai Sang,Liu Xian-Zhi,Li Wen-Cai,Zhang Rui-Qi,Li Yan-Xi,Chung Nellie Yuk-Fei,Chen Hong,Wu Jingsong,Zhou Liangfu,Li Kay Ka-Wai,Ng Ho-Keung
Acta neuropathologica
Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.
10.1007/s00401-018-1874-3