Pediatric Low-grade Glioma with FGFR1:TACC1 Fusion Mutation Displays Aggressive Tumor Biology: A Case Report and Literature Review

Abstract Background Pediatric low-grade gliomas (pLGG) are the most common childhood solid tumors. While typically indolent with excellent prognoses, certain mutations have been associated with aggressive tumor behavior. Case Presentation A 19-month-old with biopsy-confirmed pLGG experienced symptoms and progression of residual tumor two months following debulking surgery. Repeat debulking and biopsies similarly confirmed pLGG, while molecular analyses identified a FGFR1:TACC1 fusion. Discussion While rare, pLGG can exhibit aggressive tumor biology. This review highlights the role of FGFR aberrations in pLGG characterization, prognostication, and clinical decision-making. An examination of targeted therapies and ongoing clinical trials for recalcitrant pLGG was also performed. Title Page Title: Pediatric Low-grade Glioma with FGFR1:TACC1 Fusion Mutation Displays Aggressive Tumor Biology: A Case Report and Literature Review Authors: Kai Jie, Ng. 1*, Laura Shih Hui, Goh. 1,2*, Colin Kok Ann, Teo. 3, Dinesh, Nivedh. 3, Keith Gerald R, Cheng. 3, Bingcheng, Wu. 4, Miriam Santiago, Kimpo. 5, Balamurugan, Vellayappan. 6, Tan Boon, Toh. 2,7, Vincent Diong Weng, Nga. 3 *These authors contributed equally to this manuscript. Author Affiliations: 1 Yong Loo Lin School of Medicine, National University of Singapore, Singapore 2 N.1 Institute for Health, National University of Singapore, Singapore 3 Division of Neurosurgery, University Surgical Cluster, National University Hospital, Singapore 4 Department of Pathology, National University Hospital, Singapore 5 Division of Pediatric Hematology and Oncology, Department of Pediatrics, National University Hospital, Singapore 6 Department of Radiation Oncology, National University Cancer Institute, Singapore 7 Institute for Digital Medicine (WisDM), National University of Singapore, Singapore Correspondence: Dr Vincent Diong Weng Nga Division of Neurosurgery, University Surgical Cluster, 1E Kent Ridge Road, Level 8, Tower Block, S119228, Singapore. Running Title: Aggressive Pediatric LGG with FGFR1:TACC1 Fusion

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Pediatric, Glioma, Genetic, Molecular, FGFR, TACC Abbreviations Table: | CNS | Central Nervous System | | FGFR | Fibroblast Growth Factor Receptor | | HGG | High-grade Glioma | | LGG | Low-grade Glioma | | MRI | Magnetic Resonance Imaging | | pLGG | Pediatric Low-grade Glioma | | TACC | Transforming Acidic Coiled-coil Containing Protein | | WHO | World Health Organization | Previous Presentations: This paper was previously presented at the 19 th Asian Society for Neuro-Oncology (ASNO) Annual Meeting in Singapore, from 16 th -18 th August 2024. No abstract was published.

Background Pediatric low-grade gliomas (pLGG) are the most common childhood solid tumors. While typically indolent with excellent prognoses, certain mutations have been associated with aggressive tumor behavior. Case Presentation A 19-month-old with biopsy-confirmed pLGG experienced symptoms and progression of residual tumor two months following debulking surgery. Repeat debulking and biopsies similarly confirmed pLGG, while molecular analyses identified a FGFR1:TACC1 fusion.

While rare, pLGG can exhibit aggressive tumor biology. This review highlights the role of FGFR aberrations in pLGG characterization, prognostication, and clinical decision-making. An examination of targeted therapies and ongoing clinical trials for recalcitrant pLGG was also performed.

Central nervous system (CNS) tumors are the leading cause of solid tumor-related oncological morbidity in pediatric populations 1, among which the most common are pediatric low-grade gliomas (pLGG) 2 . pLGGs are a heterogeneous group of neoplasms classified as World Health Organization (WHO) grade I or II gliomas 3 . While traditionally based on histomorphological findings, the current WHO 2021 5 th edition classification of CNS tumors incorporates both molecular parameters and genetic alterations in subtyping distinct glioma entities 4,5 . Despite similarities between pediatric and adult low-grade gliomas (LGG) on a histomorphological basis, these two groups of tumors display markedly distinct clinical and molecular features, warranting classification as separate disease entities 3,4 . Notably, while alterations in BRAF and FGFR are well described driver mutations in pLGGs, these genetic findings are rarely observed in adult LGGs 3 . Furthermore, unlike adult LGG which have a significant risk of high-grade transformation, pLGGs rarely evolve into high-grade lesions 6–8 . pLGGs also demonstrate superior long-term progression-free survival 9,10, and 10-year overall survival exceeding 90% 2,6 . In view of their indolent nature, the standard of care for diffuse pLGGs in relatively less-eloquent areas of the brain involves debulking and watchful observation, with administration of adjuvant treatments reserved only for clinically or radiologically significant tumor progression 11,12 . Nevertheless, literature has described possible associations between certain molecular drivers and malignant transformation of pLGGs 8,12,13 . The FGFR1:TACC1 fusion mutation is one such molecular event, reportedly present in 1.5-7.6% of pLGGs 14, and is often associated with tumor aggression and poor prognosis in pLGGs 15,16 . However, relapse post-surgical debulking, regardless of the underlying molecular driver, are usually delayed and tends to follow high-grade transformation 8,17 . Here, we describe a novel case of a diffuse cerebellar pLGG, associated with an FGFR1:TACC1 fusion mutation, displaying uncharacteristic rapid expansion just two months post-debulking. Case Presentation A 19-month-old male presented with persistent vomiting and truncal ataxia, on a background of increasing occipitofrontal circumference crossing centiles and gross motor delay. Contrast-enhanced Magnetic Resonance Imaging (MRI) brain revealed a poorly-defined mass centered over the left cerebellum and vermis, visualized in Figures 1A-C . This was complicated by severe upstream hydrocephalus, visualized in Figure 1D. A tumor biopsy revealed a low-grade glioma negative for BRAF V600E . Suboccipital craniotomy with debulking of the cerebellar tumor was performed, and subsequent decision was made for surveillance without adjuvant therapy in view of low-grade histomorphology. MRI images post-debulking are visualized in Figures 1E-H. Two months post discharge, the 21-month-old was readmitted for relapse of symptoms. A repeat contrast-enhanced MRI brain revealed rapid expansion of the residual tumor from 5.4x4.7x5.1cm 3 to 5.6x5x5.8cm 3, visualized in Figures 1I-J . There was notable upward extension of the tumor bulk to involve the midbrain, visualized in Figures 1K-L . Repeat debulking of the tumor was performed and histopathological findings similarly showed glioma with low-grade features, as visualized in Figure 2 . Focally, there was an area of microvascular proliferation in linear arrays. Ki67 proliferation index was less than 3% in most areas but there were focal elevations at 10%. Nevertheless, the clinical significance of these findings was uncertain, and on their own these features were insufficient to classify this glioma as high-grade. Molecular studies using the Ampliseq Childhood Cancer Panel identified a FGFR1:TACC1 fusion. Post-operatively, the patient was discharged with marked improvement in symptoms. In view of the aggressive behavior despite low-grade tumor morphology, the patient was started on a chemotherapy protocol consisting of intravenous Vincristine (1.5 mg/m 2 /dose, max 2 mg, in 25 ml of normal saline over 15 min) and intravenous Carboplatin (560 mg/m 2 /dose) every 4 weeks for a total of 12 cycles 18,19 . He was monitored closely for consideration of targeted therapies.

pLGGs generally demonstrate favorable progression-free survival regardless of post-operative residual tumor size in cases of subtotal resection 20,21 . While adjuvant therapies are available, immediate post-operative radiotherapy for pLGGs confers no additional survival benefits 22, and may cause endocrinological and neurocognitive sequalae 23,24 . As such, a conservative strategy of watchful observation is preferred post-debulking of pLGGs, with deferment of adjuncts till significant clinical or radiological progression is observed 7,11,25 . Clinically appreciable tumor progression in pLGGs typically occurs years later 8,15,17, but progression was observed just two months post-debulking in this case. Unfortunately, medical management of early recurrent pLGGs in infants and young children remains highly controversial due to the lack of established guidelines and treatment modalities 26,27 . The risk of overwhelming tumor burden must be balanced against potentially debilitating sequalae of early childhood adjuvant treatment. Recent literature emphasizes the role of molecular profiling for accurate discrimination of pLGGs, which may enable the use of targeted biologics as safe and effective alternatives to conventional chemoradiotherapy, particularly for young infants who are more vulnerable to long-term sequalae 4,5 . pLGGs almost universally exhibit upregulation of the RAS/MAPK pathway 28–30, positioning MAPK -targeted molecular treatments as promising potential therapeutics for recalcitrant tumors 11 . FGFR1 aberrations are the second most common molecular drivers in pLGGs, with FGFR1:TACC1 fusion mutations inducing dimerization and persistent activation, driving growth, proliferation, and survival via MAPK and PI3K/AKT pathways 16,31 . Beyond tumorigenesis, FGFR aberrations contribute to tumor aggression and relapse, with FGFR1 fusions associated with malignant transformation, therapy resistance and poor survival outcomes in adult LGGs 32–35 . In pLGGs, FGFR1 fusions have also been associated with aggressive biology, including shorter progression-free survival and malignant transformation 15,16 . Relevant clinical trials for our case of pLGG with an FGFR1:TACC1 fusion gene encompass studies focused on recurrent pLGG and FGFR1 mutations in gliomas. In trials focusing on recurrent pLGG, the combination of dabrafenib and trametinib (NCT02684058 36, NCT02124772 37 ) has been investigated for its efficacy in managing refractory or recurrent pLGGs with BRAF V600E mutations, targeting mutated BRAF and MEK respectively. Previous trials have examined vinblastine (NCT00213278 38, NCT00575796 39 ) and Poly-ICLC (NCT01188096 40 ) for their potential role in controlling tumor progression and recurrence. Additionally, vinblastine with or without bevacizumab (NCT02840409 41 ) is currently being investigated for its efficacy in unresectable or progressive LGGs. In trials focusing on FGFR -altered cancers, erdafitinib is currently under investigation in two distinct trials for its efficacy in gliomas and other cancers with FGFR mutations. In a pan-cancer trial (NCT03210714 42 ), erdafitinib is currently evaluated for its potential in treating pediatric patients with relapsed or refractory advanced solid tumors harboring FGFR mutations. Concurrently, in adult gliomas, erdafitinib is being studied for its application in recurrent IDH-wildtype high grade gliomas (HGG) harboring FGFR-TACC fusions 43 . AZD4547, another small molecule inhibitor targeting FGFR, has been tested in several cancers, including recurrent IDH-wild type HGGs expressing FGFR-TACC gene fusion (NCT02824133 44 ). Additionally, BGJ398 (NCT01975701 45 ) was examined in a phase II trial specifically for patients with recurrent HGGs. While the era of targeted molecular treatments holds promise, clinical benefit of existing FGFR -targeted therapeutics, such as Erdafitinib, remain limited by hyperphosphatemia secondary to off-target inhibition of FGFR1, resistance mutations in FGFR genes, activation of bypass signaling pathways, and concurrent TP53 alterations 46 . Nevertheless, next-generation FGFR inhibitors therapeutics aim to address these limitations, offering hope for more effective treatments. As FGFR mutations may represent an aggressive subtype of pLGGs, further research and trials on this front are required to establish effective therapies for improved patient outcomes.

We described a case of pLGG characterized by an FGFR1:TACC1 fusion mutation and its notably aggressive tumor profile. Moving forward, studies defining the clinical implications of possible driver mutations are crucial. Such efforts are crucial to establish a comprehensive framework to manage progressive or non-resettable pLGGs. Declarations Ethics approval and consent to participate Written informed consent to participate was obtained from the patient (or their legal guardian, where applicable). Consent for publication Written informed consent for publication of this case report, including relevant medical details and images, was obtained from the patient (or their legal guardian, where applicable). Availability of data and materials The data supporting the findings of this case report are included in this published article. Further details are available from the corresponding author upon reasonable request. Conflict of Interest Statement The authors declare that they have no conflicts of interests. Funding The research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Author’s contributions KJN and LSHG and were the major contributors in reviewing literature, drafting, and revising the manuscript. CKAT, DN, KGRC, and BWQT critically reviewed and revised the manuscript. BW performed the histological examination of the low-grade glioma specimen. MSK and BV were directly involved in the care of the child and critically reviewed the manuscript. TBT and VDWN were subject-matter experts who helped conceptualize and supervise the project. All authors read and approved the final manuscript.

Not applicable. Figure Description Figure 1: MRI brain performed on the patient at various stages of management. Pre-operatively, contrast-enhanced T1-weighted axial (A) and sagittal (B) views showed a heterogeneous, irregular lesion centered in the left cerebellar hemisphere, with effacement of the 4 th ventricle, while T2-weighted axial MRI depicted tumor extension into the cerebellum and brainstem (C) and the resulting obstructive hydrocephalus (D). Post-operatively, contrast-enhanced T1-weighted axial (E & F) and sagittal (G & H) views, which showed the resultant residual tumor with increased enhancement post-resection. On readmission, contrast-enhanced T1-weighted axial (I & J) and sagittal views (K & L) showed tumor progression into the midbrain superiorly, with the tumor demonstrating a more cystic appearance in this study. Figure 2: Histopathological findings of repeat posterior fossa tumor biopsy. The tumor histology showed low-to-moderate cellularity with myxoid stroma, neoplastic glial cells demonstrating ovoid-to-elongated nuclei without pleomorphism, and inconspicuous mitotic activity (A). Focal microvascular proliferation in linear arrays was visualized (B). Most areas showed a low Ki67 proliferation index of 3% (C), but focal areas of high Ki67 proliferation index of 10% were visualized (D).

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Authors Metrics & Citations Metrics Article Usage 635views 198downloads Citations Download citation Ng Kai Jie, Goh Laura Shih Hui, Teo Colin Kok Ann, et al. Pediatric Low-grade Glioma with FGFR1:TACC1 Fusion Mutation Displays Aggressive Tumor Biology: A Case Report and Literature Review. Authorea. 07 January 2025. DOI: https://doi.org/10.22541/au.173623241.19851384/v1 DOI: https://doi.org/10.22541/au.173623241.19851384/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.