{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T13:37:23Z","timestamp":1769175443562,"version":"3.49.0"},"reference-count":21,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>Alterations involving the mitogen-activated protein kinase (MAPK) pathway are central drivers of pediatric and adult low-grade gliomas (LGGs), with BRAF fusions representing a dominant oncogenic mechanism in pilocytic astrocytoma. While KIAA1549::BRAF remains the most prevalent fusion, an expanding repertoire of alternative fusion partners continues to refine the molecular landscape of MAPK-driven gliomas and has important therapeutic implications. Here, we report a previously unrecognized ASAP1::BRAF fusion identified in a young adult with a World Health Organization grade 1 temporal lobe pilocytic astrocytoma, highlighting both its biological plausibility and potential relevance for targeted therapy. A 31-year-old female presented with new-onset seizures and underwent gross total resection of a well-circumscribed, partially cystic left temporal lobe tumor. Histopathological and immunohistochemical findings were consistent with pilocytic astrocytoma, demonstrating low proliferative activity and absence of high-grade features. Comprehensive molecular profiling using RNA-based next-generation sequencing revealed an in-frame ASAP1 exon 29::BRAF exon 9 fusion, preserving the intact C-terminal BRAF kinase domain while eliminating N-terminal regulatory regions. No additional pathogenic variants were detected. To substantiate the structural authenticity of the fusion, deep learning\u2013based breakpoint validation using FusionAI was performed, yielding a high fusion probability score and supporting a bona fide genomic rearrangement rather than an RNA-sequencing artifact. Genomic feature annotation demonstrated enrichment of repetitive elements, regulatory regions, and chromatin accessibility features flanking the breakpoint, consistent with known mechanisms of fusion gene formation. Functionally, the ASAP1::BRAF fusion is predicted to emphasize constitutive MAPK pathway activation via dimer-dependent BRAF signaling, analogous to canonical BRAF fusions and mechanistically distinct from BRAF V600E mutations. Clinically, BRAF fusion\u2013driven tumors are typically resistant to first-generation BRAF inhibitors but may be sensitive to MEK inhibitors or emerging type II RAF inhibitors that effectively target RAF dimers. Although no adjuvant therapy was required following complete resection, documentation of this fusion provides a rational framework for future molecularly guided treatment should disease recurrence occur. This case expands the spectrum of oncogenic BRAF fusion partners in LGG and underscores the importance of integrated RNA-based diagnostics and computational validation in precision neuro-oncology.<\/jats:p>","DOI":"10.3389\/fonc.2026.1763047","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T12:38:11Z","timestamp":1769171891000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Novel ASAP1::BRAF fusion in a young adult with low-grade temporal lobe glioma"],"prefix":"10.3389","volume":"16","author":[{"given":"Petroula","family":"Gerasimou","sequence":"first","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitris","family":"Vrachnos","sequence":"additional","affiliation":[{"name":"Stremble Ventures Ltd.","place":["Limassol, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiannos","family":"Kyprianou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agathi","family":"Elpidoforou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andri","family":"Miltiadous","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andri","family":"Mitsidou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katerina","family":"Nicolaou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriella","family":"Shianiou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Zartila","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Ioannou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Christofi","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Efi","family":"Georgiou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chrysanthi","family":"Avgousti","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Kanezou","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Johnson","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Varnavas","family":"Papanastassiou","sequence":"additional","affiliation":[{"name":"Neurosurgery Department, Aretaieio Hospital","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Oxinou","sequence":"additional","affiliation":[{"name":"Christina Oxinou Histopathology\/Cytology Laboratory","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marilena","family":"Theodorou","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology & Nuclear Medicine, Bank of Cyprus Oncology Center","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna Maria","family":"Shiarli","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology & Nuclear Medicine, Bank of Cyprus Oncology Center","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Athos","family":"Antoniades","sequence":"additional","affiliation":[{"name":"Stremble Ventures Ltd.","place":["Limassol, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianxiang","family":"Chi","sequence":"additional","affiliation":[{"name":"Molecular Hematology-Oncology Department, Karaiskakio Foundation","place":["Nicosia, Cyprus"]},{"name":"Centre for the Study of Haematological and other Malignancies","place":["Strovolos, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Costeas","sequence":"additional","affiliation":[{"name":"Centre for the Study of Haematological and other Malignancies","place":["Strovolos, Cyprus"]},{"name":"Karaiskakio Foundation","place":["Nicosia, Cyprus"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2015.00054","article-title":"Current understanding of BRAF alterations in diagnosis, prognosis and therapeutic targeting in paediatric low grade gliomas","volume":"5","author":"Penman","year":"2015","journal-title":"Front Oncol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2020.03.011","article-title":"Integrated molecular and clinical analysis of 1,000 pediatric low-Grade gliomas","volume":"37","author":"Ryall","year":"2020","journal-title":"Cancer Cell"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-023-00359-y","article-title":"Integrated molecular and clinical analysis of BRAF-mutant glioma in adults","volume":"7","author":"Schreck","year":"2023","journal-title":"NPJ Precis Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/jnen\/nlab110","article-title":"Novel RAF fusions in pediatric low-grade gliomas demonstrate MAPK pathway activation","volume":"80","author":"Lind","year":"2021","journal-title":"J Neuropathology Exp Neurol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1136\/jcp-2023-209318","article-title":"Clinicopathological analysis of BRAF and non-BRAF MAPK pathway-altered gliomas in paediatric and adult patients: a single-institution study of 40 patients","author":"Ali","year":"2024","journal-title":"J Clin Pathol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.21037\/tp-23-541","article-title":"Advances in the treatment of BRAF-mutant low-grade glioma with MAPK inhibitors","volume":"13","author":"Houghton","year":"2024","journal-title":"Trans Pediatr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2025.1520316","article-title":"Integrating MAPK pathway inhibition into standard-of-care therapy for pediatric low-grade glioma","volume":"15","author":"Crotty","year":"2025","journal-title":"Front Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2021.103164","article-title":"FusionAI: Predicting fusion breakpoint from DNA sequence with deep learning","volume":"24","author":"Kim","year":"2021","journal-title":"IScience"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2022.101185","article-title":"FusionAI, a DNA-sequence-based deep learning protocol reduces the false positives of human fusion gene prediction","volume":"3","author":"Kim","year":"2022","journal-title":"STAR Protoc"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab1056","article-title":"FusionGDB 2.0: Fusion gene annotation updates aided by deep learning","volume":"50","author":"Kim","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-2097","article-title":"Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas","volume":"68","author":"Jones","year":"2008","journal-title":"Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1172\/JCI33656","article-title":"BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas","volume":"118","author":"Pfister","year":"2008","journal-title":"J Clin Invest"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1101\/gr.164806.113","article-title":"Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability","volume":"24","author":"Akagi","year":"2014","journal-title":"Genome Res"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1101\/gad.351051.123","article-title":"LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities","volume":"37","author":"Mendez-Dorantes","year":"2023","journal-title":"Genes Dev"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2941","article-title":"The biogenesis of chromosome translocations","volume":"16","author":"Roukos","year":"2014","journal-title":"Nat Cell Biol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1101\/gr.229401.117","article-title":"Predicting human genes susceptible to genomic instability associated with Alu\/Alu-mediated rearrangements","volume":"28","author":"Song","year":"2018","journal-title":"Genome Res"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi265","article-title":"Mechanisms of common fragile site instability","volume":"14","author":"Glover","year":"2005","journal-title":"Hum Mol Genet"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1080\/19491034.2022.2143106","article-title":"Chromatin accessibility: methods, mechanisms, and biological insights","volume":"13","author":"Mansisidor","year":"2022","journal-title":"Nucleus"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2019.01.024","article-title":"R-loops as cellular regulators and genomic threats","volume":"73","author":"Crossley","year":"2019","journal-title":"Mol Cell"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/nrg3152","article-title":"Transcription as a source of genome instability","volume":"13","author":"Kim","year":"2012","journal-title":"Nat Rev Genet"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2019.09.009","article-title":"Genetic heterogeneity of BRAF fusion kinases in melanoma affects drug responses","volume":"29","author":"Botton","year":"2019","journal-title":"Cell Rep"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1763047\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T12:38:13Z","timestamp":1769171893000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1763047\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":21,"alternative-id":["10.3389\/fonc.2026.1763047"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1763047","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,23]]},"article-number":"1763047"}}