Gliomas Of Childhood Research Articles

Glioma of the anterior visual pathway in children. Part II. Current treatment trends

The literature review presents modern treatment aspects for anterior optic pathway gliomas (OPGs), which are low-grade brain tumors accounting for 20%–30% of childhood gliomas, can occur anywhere along the visual pathways and in the development of the surrounding structure, and are predominantly benign. The predominant histological type of tumor in this localization is piloid astrocytoma (PA), less commonly pilomyxoid astrocytoma (PMA). However, the course of anterior OPGs is unpredictable and varies from spontaneous regression to progression with severe visual, neurological, and endocrine disorders, affecting treatment and disease prognosis. Although there have been advances in clinical studies based on histological and molecular genetic analyses, no fundamental changes in survival rates and recurrence-free periods and improvements in functional outcomes have been achieved. Furthermore, no studies have comprehensively analyzed the functional results depending on the management tactics of pediatric patients with anterior visual pathway gliomas. Anterior optic pathway glioma treatment is challenging and complex problem, which depends on the patient’s age, clinical picture, localization, surgical resectability, and histological and molecular genetic study results. It includes surgical treatment, chemotherapy, radiation therapy, the use of targeted therapy drugs, and additional advanced techniques that are still under development and research. Optimal treatment of anterior optic pathway gliomas in children remains a topic of discussion in the current literature.

Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.

Midline low-grade gliomas (mLGGs) of early childhood have a poorer prognosis compared with tumors of other localizations and in older patients. LGGs are associated with aberrant activation of RAS-RAF-MEK pathway, and pharmacological inhibition of the pathway has therapeutic promise. The aim of this study was clinical and molecular characterization of infantile mLGGs, with emphasis on the efficacy of targeted kinase inhibition. This study enrolled 40 patients with mLGG age <3 years. The majority of the patients (30/40) received first-line chemotherapy (CT) as per International Society of Paediatric Oncology LGG 2004 guidelines. In all patients, molecular genetic investigation of tumor tissue by polymerase chain reaction and RNA sequencing was performed. The median follow-up was 3.5 years. First-line CT failed in 24 of 30 recipients. The identified molecular profiles included KIAA1549::BRAF fusions in 26 patients, BRAF V600E in six patients, FGFR1::TACC1 fusions in two patients, and rare fusion transcripts in four patients. At disease progression, targeted therapy (TT) was initiated in 27 patients (22 patients received trametinib) on the basis of molecular findings. TT was administered for a median of 16 months, with partial response achieved in 12 of 26 (46%) patients in which response was evaluated. Severe adverse events were detected only on trametinib monotherapy: acute damage of GI or urinary mucosa complicated by hemorrhage and development of transfusion-dependent anemia in four patients and grade 3 skin toxicity in three patients. mLGGs of early childhood are often aggressive tumors, resistant to CT, and frequently require alternative treatment. The majority of patients harbor druggable molecular targets and respond to molecular TT.

Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study.

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

Pediatric brain tumors

Pediatric central nervous system (CNS) tumors differ in their relative frequency, location, histology, biological behavior and prognosis from tumors in adults. Accurate neuropathological classification of CNS tumors is essential for therapeutic decisions and inclusion in therapy optimization studies. Tissue samples are analyzed by standardized conventional histological, immunohistological and molecular pathological methods and diagnosed according to the current World Health Organization (WHO) classification for CNS tumors (2021). By identifying characteristic genetic alterations and specific epigenetic signatures, the precision in the classification of pediatric brain tumors has significantly improved in recent years. The WHO classification allows aworldwide uniform, standardized classification of brain tumors and forms the basis for comparability of international epidemiological and clinical data. In some tumor types, such as childhood gliomas and embryonal tumors, key molecules and signaling pathways have been identified in recent years that represent starting points for new mechanism-based therapeutic modalities in the treatment of these patients.

Evolving therapies, neurocognitive outcomes, and functional independence in adult survivors of childhood glioma.

Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown. Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided. Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory. Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions.

Multi-ancestry genome-wide association study of 4,069 children with glioma identifies 9p21.3 risk locus.

While recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric CNS tumors have been identified to date. Meta-analysis of three population-based genome-wide association studies (GWASs) comprising 4,069 children with glioma and 8,778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort. Quantitative trait loci analyses and a transcriptome-wide association study were conducted to assess possible links with brain tissue expression across 18,628 genes. Common variants in CDKN2B-AS1 at 9p21.3 were significantly associated with astrocytoma, the most common subtype of glioma in children (rs573687, p-value 6.974e-10, OR 1.273, CI95 1.179-1.374). The association was driven by low-grade astrocytoma (p-value 3.815e-9) and exhibited unidirectional effects across all six genetic ancestries. For glioma overall, the association approached genome-wide significance (rs3731239, p-value 5.411e-8), while no significant association was observed for high-grade tumors. Predicted decreased brain tissue expression of CDKN2B was significantly associated with astrocytoma (p-value 8.090e-8). In this population-based GWAS meta-analysis, we identify and replicate 9p21.3 (CDKN2B-AS1) as a risk locus for childhood astrocytoma, thereby establishing the first genome-wide significant evidence of common variant predisposition in pediatric neuro-oncology. We furthermore provide a functional basis for the association by showing a possible link to decreased brain tissue CDKN2B expression and substantiate that genetic susceptibility differs between low- and high-grade astrocytoma.

Association of TP53 rs1042522 C>G Polymorphism with Glioma Risk in Chinese Children.

Glioma is the most common intracranial malignancy. TP53 is a crucial tumor suppressor gene that plays an essential regulatory role in cell growth, apoptosis, and DNA repair. The TP53 rs1042522 C>G polymorphism has been reported to be strongly associated with various tumor risks. To assess the TP53 rs1042522 C>G polymorphism with glioma risk in Chinese children, we determined the genotypes of the TP53 rs1042522 C>G polymorphism in 171 glioma patients and 228 cancer-free controls by Taqman assay. We assessed the association of the polymorphism with glioma risk using odds ratio (OR) and 95% confidence interval (CI) generated by logistic regression models. We also performed stratified analyses by age, gender, tumor subtypes, and clinical stages, but no significant association was detected between TP53 rs1042522 C>G polymorphism and childhood glioma risk. These results suggest that the TP53 rs1042522 C>G polymorphism is not associated with glioma risk in Chinese children. Subsequent studies with a larger sample size are needed to validate our results.

LGG-41. The clinical and molecular landscape of gliomas in adolescents and young adults

OBJECTIVE: Gliomas in adolescents and young adults (AYA) are commonly treated with a standard chemo-radiation approach based on data from adults. The clinical impact of paediatric-type alterations in these tumours is unknown. METHODS: We compiled a multi-institutional cohort of patients diagnosed with glioma between 15-39.9 years over 20 years. Complete molecular analysis, therapeutic data and outcome was collected. For specific alterations, analysis included patients aged 0-39.9 years. RESULTS: A total of 1900 patients with 876 AYA gliomas were included. Ongoing analysis reveals genetic alterations in 95% of available tumours. IDH-mutant tumours account for only 53%, while paediatric-type mutations were found in 35% of AYA tumours with IDH-WT GBM accounting for the remaining 12%. The most common paediatric alterations in AYAs included BRAF p.V600E (11%) and FGFR alterations (6%) while BRAF fusions, H3 p.K27M and H3.3 p.G34R were rarely observed (4%, 4% and 1% respectively). BRAF fused tumours with non-canonical binding partners were enriched in AYAs. Analysis of BRAF-V600E gliomas between ages 0-40 revealed increased tendency for malignant tumours in patients >20 years suggesting malignant transformation possibly due to higher rate of secondary hits including TP53, CDKN2A and ATRX mutations. This resulted in worse overall-survival for AYA patients with BRAF-V600E glioma when compared to children under 20 years (p=0.0032). Ten-year OS of 100%, 90% and 95% was seen for BRAF fused, BRAF-V600E and FGFR-altered AYA low grade glioma respectively, compared to 14% and 25% for BRAF-V600E and FGFR-altered high grade glioma. In contrast, continuous decline was observed in the IDH-mutant gliomas with 10-year OS of 50% which declined to 29% at 15 years. CONCLUSIONS: Gliomas in AYA are enriched for paediatric-type alterations with distinct molecularly-based outcomes. As these tumours carry different outcomes than childhood glioma and may respond to targeted inhibitors, AYA gliomas would benefit from comprehensive diagnostic and therapeutic approaches.

LGG-15. Late mortality and morbidity of adult survivors of childhood glioma treated across three decades: a report from the Childhood Cancer Survivor Study

PURPOSE: Pediatric low-grade glioma therapy has evolved to delay or eliminate radiation. The impact of therapy changes on long-term outcomes remains unknown. METHODS: Cumulative incidence of late mortality (death >5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, CTCAE grading criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed 1970-1999. Outcomes were evaluated by diagnosis decade and by treatment exposures received ≤5 years following diagnosis (surgery-only, chemotherapy ± surgery, and cranial radiation ± surgery or chemotherapy). Relative risk (RRs) with 95%CIs estimated long-term outcomes using multivariable piecewise exponential models. RESULTS: Among 2,684 eligible survivors (age at diagnosis (median [range]), 7 years [0-20 years]; time from diagnosis, 24 years [5-48 years]), exposure to cranial radiation decreased [51% (1970s), 45% (1980s), 25% (1990s)] along with late tumor recurrence (>5 & ≤15 years from diagnosis) [9.8% (1970s), 8.8% (1980s), 5.0% (1990s)]. The 15-year cumulative incidence of late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p<0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence of grade 3-5 CHCs was 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p<0.0001). A reduction in SN incidence was not observed. In multivariable analyses excluding treatment exposure, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality, grade 3-5 CHCs and SNs. Inclusion of treatment exposure in the model attenuated the effect of diagnosis decade. Radiation or chemotherapy exposure increased risk compared to surgery alone for late mortality (radiation RR 4.95, 95%CI 3.79-6.47; chemotherapy RR 2.88, 95%CI 1.85-4.48), CHCs (radiation RR 4.02, 95%CI 3.28-4.94; chemotherapy RR 1.66, 95%CI 1.13-2.45), and SNs (radiation RR 4.02, 95%CI 3.06-6.13, chemotherapy RR 2.08, 95%CI 1.03-4.23)). CONCLUSION: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.

HGG-21. Oncogenic tyrosine kinase gene fusions in infant-type hemispheric gliomas - comparison of RNA- and DNA-based methods for their reliable detection

High-grade diffuse gliomas (HGG) in early childhood are characterized by a more favorable outcome compared to older children. We demonstrated in previous studies that these tumors have stable genomes. Activating tyrosine kinase gene fusions in infant-type hemispheric gliomas represent therapeutic targets. 50 supratentorial HGG occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, Bonn University. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified on the DNA level by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET and Molecular Inversion Probe (MIP) methodology. On the RNA level, fusion transcripts were detected by targeted RNA sequencing as well as Nanostring assay with fusion-specific probes. 37 supratentorial HGG occurred in the first year of life, 13 HGG between one and four years. 18 cases showed fusions of ALK to different partners; all occurred in the first year of life (18/37, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two cases novel fusions. The different methods led to comparable results. Only recurrent fusions with known fusion partners were detectable with fusion sequence-specific Nanostring probes and library construction for targeted RNA sequencing failed in a fraction of cases. Break-apart FISH led to reliable results on the next day, and MIP technology represented the most sensitive method for analysis of FFPE samples. Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of HGG of young children; most frequent were ALK fusions occurring in tumors of infants. DNA-based MIP technology represented the most robust and sensitive assay. A combination of RNA- and DNA-based methods to detect these fusions with high reliability is recommended.

LGG-24. Neurocognitive impairment and functional independence in adult survivors of childhood glioma: A report from the Childhood Cancer Survivor Study (CCSS)

PURPOSE: Survivors of pediatric glioma are at risk of developing physical and neurocognitive sequelae secondary to their tumor and its treatment. The contribution of these conditions to attainment of functional independence has not previously been examined. METHODS: 1,284 adult survivors of pediatric glioma (48% male, median [range] 30 [18-51] years at assessment, 22 [15-34] years since diagnosis) completed the CCSS Neurocognitive Questionnaire with impairment defined as scores > 90th %ile of sibling norms. Treatment exposures were categorized as surgery only, chemotherapy (± surgery), or cranial radiation (± chemotherapy/surgery). Self-reported chronic health conditions (CHCs) were graded by organ system using NCI’s CTCAE v4.3. Latent class analysis utilized six factors (employment, marital status, independent living, driver’s license, assistance with routine needs, assistance with personal care needs) to identify classes of functional independence. Multivariable modified Poisson regression evaluated relative risk (RR) of neurocognitive impairment between the classes, adjusting for sex, race, age at assessment, and age at diagnosis. Path analysis explored the impact of treatment exposures on functional independence, mediated by Grade 2-4 CHCs and neurocognitive impairment. RESULTS: Three latent classes of functional independence were identified: independent (58%), moderately independent (20%), and non-independent (22%). Compared to the independent class, non-independent survivors were at elevated risk for impaired task efficiency (RR=3.86, 95% CI, 2.97-5.01), memory (RR=2.39, 95% CI, 1.91-2.98), organization (RR=2.04, 95% CI, 1.64-2.54), and emotional regulation (RR=1.67, 95% CI, 1.30-2.15). Path analysis revealed significant direct paths from cranial radiation (β=0.14), impaired task efficiency (β=0.42), and sensorimotor (β=0.22) and endocrine conditions (β=0.24) to non-independence. Cranial radiation also was indirectly associated with non-independence through impaired task efficiency (β=0.06), and sensorimotor (β=0.06) and endocrine conditions (β=0.10). CONCLUSIONS: Neurocognitive impairment and chronic health conditions partially mediate the association between treatment exposures and attainment of independence in adulthood, identifying potential intervention targets to promote independence in long-term survivors.

Late mortality and morbidity among adult survivors of childhood glioma treated over three decades: A report from the Childhood Cancer Survivor Study.

10007 Background: Therapy for pediatric low-grade glioma has evolved to delay or eliminate the need for cranial radiation. The impact of this change in approach on long-term outcomes remains unknown. Methods: Cumulative incidence of late mortality (death ≥5 years from diagnosis), subsequent neoplasms (SNs), and chronic health conditions (CHCs, graded using CTCAE criteria) were evaluated in the Childhood Cancer Survivor Study among 5-year survivors of glioma diagnosed between 1970 and 1999. Outcomes were evaluated by diagnosis decade (1970s, 1980s, 1990s) and by treatment exposure in the first five years from diagnosis [surgery only, chemotherapy (with or without surgery), and cranial radiation (with or without surgery or chemotherapy)]. Relative Risk (RRs) with 95% CIs estimated long-term outcomes using multivariable piecewise exponential models. Results: Among 2,684 eligible survivors (median age at diagnosis, 7 years [range, 0 to 20 years]; median time from diagnosis, 24 years [range, 5 to 48 years]), the proportion exposed to cranial radiation decreased from 51% (1970s) to 45% (1980s) and 25% (1990s) while the rate of recurrence within &gt; 5 years but ≤15 years of diagnosis decreased from 9.8% (1970s) to 8.8% (1980s) and 5.0% (1990s). The 15-year cumulative incidence rate of all-cause late mortality was 10.3% (1970s), 6.5% (1980s), and 6.0% (1990s) (p &lt; 0.001, comparison of cumulative incidence curves). The 15-year cumulative incidence rates of severe, disabling or life-threatening (grade 3-5) CHCs also decreased between 1970 and 1999: 19.7% (1970s), 17.8% (1980s), and 14.2% (1990s) (p &lt; 0.0001). Lower rates of SN were not observed. In a multivariable analysis adjusted for age at diagnosis, attained age, race, sex and diagnosis decade, later diagnosis (1990s vs. 1970s) was associated with lower risk of late mortality (RR 0.86, 95% CI 0.74-0.99), grade 3-5 CHCs (RR 0.65, 95% CI 0.51-0.82) and SN (RR 0.64, 95% CI 0.44-0.94). In addition, when treatment exposure was added to the multivariable model, the effect of diagnosis decade was attenuated and no longer significant. Exposure to radiation or chemotherapy both increased risk compared to surgery alone: all-cause mortality (radiation RR 4.95, 95% CI 3.79-6.47; chemotherapy RR 2.88, 95% CI 1.85-4.48), grade 3-5 CHCs (radiation RR 4.02, 95% CI 3.28-4.94; chemotherapy RR 1.66, 95% CI 1.13-2.45), SNs (radiation RR 4.02, 95% CI 3.06-6.13, chemotherapy RR 2.08, 95% CI 1.03-4.23)). The effect of delayed radiation (&gt; 1year to ≤5 years from diagnosis) on all-cause late mortality, grade 3-5 CHCs, or SNs was not different compared to radiation within one year of diagnosis. Conclusions: Late mortality and CHCs decreased in childhood glioma survivors diagnosed from 1970-1999 largely due to therapy changes, particularly avoidance of cranial radiation, without increased late recurrence.

The impact of the COVID-19 pandemic on paediatric glioma patients in low, middle, and high-income countries: a multicentre, international, observational cohort study

AimsPaediatric cancer is a leading cause of non-communicable disease deaths for children worldwide, with more than 90% of deaths occurring in low-and-middle-income countries (LMICs). The COVID-19 pandemic may have exacerbated disparities in paediatric cancer outcomes between LMICs and HICs. The World Health Organization (WHO) Global Initiative for Childhood Cancer has identified gliomas as a common cancer that can act as a benchmark for assessing global paediatric cancer care. This study aims to ascertain the short and medium-term outcome across 17 countries during the COVID-19 pandemic by determining 30- and 90-day all-cause mortality rates for paediatric glioma patients who underwent treatment.MethodA multicentre, international, mixed- (retrospective and prospective), collaborative cohort study in 17 countries. Patients were recruited between March 12th 2020 and July 12th 2020.Results129 patients were recruited with the majority being histologically diagnosed as low-grade gliomas (n = 86/118, 72.9%). Seven children had a change to their planned chemotherapy treatment because of the COVID-19 pandemic. Similarly, seven children and eleven children had a change to their planned radiotherapy treatment and surgical treatment respectively because of the COVID-19 pandemic. Five patients died within the 30-day follow-up period, with all five patients being in LMICs. A sixth child, also in a LMIC, died within the 90-day follow-up period. This significant difference in mortality between LMICs and HICs was present when controlling for confounding for factors such as grade, ASA status, sex, weight, and age. ConclusionThere has been relatively minimal change to the treatment of paediatric gliomas worldwide compared to their initial planned care. There was a significant difference in mortality for childhood gliomas between LMICS and high-income countries during the COVID-19 pandemic. There needs to be a concerted effort to improve equity in health outcomes globally.

Gliomas in children and adolescents: investigation of molecular alterations with a potential prognostic and therapeutic impact.

Gliomas represent the most frequent central nervous system (CNS) tumors in children and adolescents. However, therapeutic strategies for these patients, based on tumor molecular profile, are still limited compared to the wide range of treatment options for the adult population. We investigated molecular alterations, with a potential prognostic marker and therapeutic target in gliomas of childhood and adolescence using the next-generation sequencing (NGS) strategy. We selected 95 samples with initial diagnosis of glioma from patients treated at Pediatric Oncology Institute-GRAACC/UNIFESP. All samples were categorized according to the 2021 World Health Organization Classification of Tumors of the CNS, which included 39 low-grade gliomas (LGGs) and 56 high-grade gliomas (HGGs). Four HGG samples were classified as congenital glioblastoma (cGBM). NGS was performed to identify somatic genetic variants in tumor samples using the Oncomine Childhood Cancer Research Assay® (OCCRA®) panel, fromThermo Fisher Scientific®. Genetic variants were identified in 76 of 95 (80%) tumors. In HGGs, the most common molecular alteration detected was H3F3A c.83A > T variant (H3.3 K27M) and co-occurring mutations in ATRX, TP53, PDGFRA, MET, and MYC genes were also frequently observed. One HGG sample was reclassified as supratentorial ependymoma ZFTA-fusion positive after NGS was performed. In LGGs, four KIAA1549-BRAF fusion transcripts were detected and this alteration was the most recurrent genetic event and favorable prognostic factor identified. Additionally, genetic variants in ALK and NTRK genes, which provide potential targets for therapy with Food and Drug Administration-approved drugs, were identified in two different cases of cGBM that were classified as infant-type hemispheric glioma, a newly recognized subgroup of pediatric HGG. Molecular profiling by the OCCRA® panel comprehensively addressed the most relevant genetic variants in gliomas of childhood and adolescence, as these tumors have specific patterns of molecular alterations, outcomes, and effectiveness to therapies.

HGG-28. ONCOGENIC TYROSINE KINASE GENE FUSIONS IN SUPRATENTORIAL HIGH GRADE GLIOMAS OF YOUNG CHILDREN - COMPARISON OF RNA- AND DNA-BASED METHODS FOR THEIR RELIABLE DETECTION

Abstract High-grade diffuse gliomas in early childhood are characterized by a more favorable outcome compared to older children. We have shown in previous studies that these tumors are characterized by stable genomes. The occurrence of tyrosine kinase gene fusions in high-grade gliomas of infancy may represent therapeutic targets. 50 glioblastomas (GBM) with supratentorial location occurring in children younger than four years were retrieved from the archives of the Brain Tumor Reference Center, Institute of Neuropathology, Bonn University. DNA and RNA were extracted from FFPE tumor samples. Gene fusions were identified on the DNA level by FISH using break-apart probes for ALK, NTRK1, -2, -3, ROS1 and MET and Molecular Inversion Probe (MIP) methodology. On the RNA level, fusion transcripts were detected by targeted RNA sequencing as well as Nanostring assay with fusion-specific probes. 37 supratentorial GBM occurred in the first year of life, 13 GBM between one and four years. 18 cases showed fusions of ALK to different partners; all occurred in the first year of life (18/37, 48.6%). Fusions of ROS1 were found in 5, MET in 3, NTRK1, -2, -3 in 10 cases. 12 cases showed no and two cases novel fusions. The different methods led to comparable results. Only recurrent fusions with known fusion partners were detectable with fusion sequence-specific Nanostring probes and library construction for targeted RNA sequencing failed in a fraction of cases. Break-apart FISH led to reliable results on the next day, and MIP technology represented the most sensitive method for analysis of FFPE samples. Gene fusions involving the tyrosine kinase genes ALK, MET, ROS1 and NTRK1, -2, -3 occurred in 72% of glioblastomas of young children; most frequent were ALK fusions occurring in infant GBM. DNA-based MIP technology represented the most robust and sensitive assay. A combination of RNA- and DNA-based methods to detect these fusions with high reliability is recommended.

Stem cell models help crack regional oncohistone codes driving childhood gliomas.

In this issue of Cell Stem Cell, Funato etal. (2021) and Bressan etal. (2021) use stem cells as models to define functions of the histone H3.3 G34R mutation in childhood gliomas. Both studies find strong regional specificity to oncohistone activity and implicate specific elements of an aberrantly locked-in neural progenitor transcriptional circuitry.

Çocukluk Çağında Karşılaşılan Sinir Sistemi Yüksek Dereceli Glial Tümörleri ve Tedavisi

High-grade gliomas in childhood are difficult to treat and have a very poor prognosis. For decades, reliable radical surgery and radiation therapy have been the cornerstones of treatment for these cancers. For most children, however, these treatments provide short-term clinical benefits and disease control, and most patients relapse within 2 years. Infiltration properties and resistance to radiation therapy are considered characteristics that determine the unpleasant course of these tumors. There is currently no effective chemotherapy regimen to treat these cancers, but many new treatment options are being actively explored.

Management of pediatric cervicomedullary astrocytoma

Cervicomedullary astrocytomas are low grade gliomas of childhood and young age which are typically centered at the junction of brainstem and cervical spine and present with a long duration of symptoms. The diagnosis of cervicomedullary astrocytomas is normally delayed as these tumours are slow growing and patients present with a long duration of symptoms. The symptoms are typical and can be correlated to the location of the tumour. Histopathology and Immunohistochemistry(IHC) guides us proving the diagnosis. Management of cervicomedullary astrocytomas includes surgery, radiotherapy and chemotherapy. A 13 years old female child presented with complaints of headache, vomiting, neck pain and progressive neck tilt. MRI of brain and cervical spine revealed moderate to significant expansile lesion in the dorsal aspect of lower medulla, cervicomedullary junction and the upper cervical cord upto C4-5 disc level.She underwent subtotal resection of the tumour. Histopathology and IHC confirmed her diagnosis as Astrocytoma WHO Grade-II. Patient underwent adjuvant radiation treatment to a radiation dose of 54 Grey in 27 fractions by Volumetric modulated arc therapy(VMAT) technique over a period of 6 weeks to the gross residual tumour and post-op tumour bed. Patient tolerated the treatment well. Patient experienced mild symptoms like nausea and vomiting during the course of treatment but well managed with supportive medications.

LGG-55. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION

Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p<0.001). These responses were rapid (median, 4 months), and sustained in 86% of tumors up to 5 years while on therapy. PLGG which discontinued BRAFi, 76.5% (13/17) progressed rapidly after discontinuation (median 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with a lack of response to BRAFi. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95%CI, 35.3% to 69.5%) vs 29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively (p=0.02). The use of BRAFi results in robust and durable responses while on therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy in childhood gliomas.

BIOM-17. BRAF MUTATION IS AN EARLY EVENT IN THE EVOLUTION OF A SUBSET OF GLIOBLASTOMAS AND IS ASSOCIATED WITH INCREASED PD-L1 EXPRESSION

Abstract INTRODUCTION BRAF is a RAF-family kinase that regulates MAPK/ERK signaling. Activating BRAF mutations, including V600E, are common in circumscribed low-grade gliomas of childhood and young adulthood, but are uncommon in infiltrative astrocytomas, including glioblastoma. Their role in glioblastoma initiation and progression requires analysis of large datasets given the low frequency (1.0%) in TCGA IDH-wild-type glioblastomas. METHODS Molecular profiling was done on 4679 FFPE gliomas by next-generation sequencing at Caris Life Sciences, of which 3170 underwent RNA-sequencing for gene fusion and 4603 DNA-sequencing for mutations. MGMT promoter methylation was tested by pyrosequencing and PD-L1 IHC was performed using the SP142 clone. RESULTS Excluding variants of uncertain significance, BRAF mutations/fusions were most common in pleomorphic xanthoastrocytoma (PXA; N=12/24, 50%), glioneuronal tumors (N=6/13, 46%), pilocytic astrocytoma (PA; N=15/48, 31%), and ganglioglioma (n=5/18, 28%). BRAF fusions were uncommon (N=17), most frequent in PA (N=8/31, 26%) where they were associated with older age at daignosis (P=0.043), and typically involved KIAA1549 as fusion partner (70%). BRAF-mutated/fused glioblastoma patients (N=59/3126, 2%) were younger than BRAF-wild-type glioblastoma patients (54 versus 59 years, P=3.5x10-3); more likely to be MGMT-unmethylated (75% versus 56%, P=5.0x10-3); and 3x more likely to express PD-L1 (55% versus 17%, P=2.1x10-10). In tumors harboring a V600E mutation, the variant allele frequency (VAF) was similar in glioblastoma as in PXA, PA, ganglioglioma, and glioneuronal tumors (median VAF=35%). CONCLUSIONS BRAF-mutated glioblastoma were 3x more likely to express PD-L1 than BRAF-wild-type glioblastoma. We observed no differences in BRAF V600E clonality in BRAF-mutated glioblastoma compared to BRAF-mutated PXA, PA, ganglioglioma, and glioneuronal tumors, suggesting BRAF mutation is an initiating event in the clonal evolution of a subset of glioblastoma. There is rationale to evaluate combined BRAF inhibition with checkpoint inhibition in BRAF-mutated glioblastoma, potentially synergizing the complete response profile of the former with the durable response profile of the latter.