{"doi":"10.1200/jco.2014.58.3922","title":"<i>BRAF</i> Mutation and <i>CDKN2A</i> Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma","abstract":"<jats:sec><jats:title>Purpose</jats:title><jats:p> To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). </jats:p></jats:sec><jats:sec><jats:title>Patients and Methods</jats:title><jats:p> We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. </jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p> sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P &lt; .001 and P &lt; .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). </jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p> BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG. </jats:p></jats:sec>","journal":"Journal of Clinical Oncology","year":2015,"id":667037,"datarank":0.8494440720203921,"base_score":5.662960480135946,"endowment":5.662960480135946,"self_citation_contribution":0.8494440720203921,"citation_network_contribution":0.0,"self_endowment_contribution":0.8494440720203921,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":287,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1741942,"name":"Nataliya Zhukova","orcid":null,"position":1,"is_corresponding":false},{"id":40077,"name":"Daniele Merico","orcid":"0000-0002-3728-4401","position":2,"is_corresponding":false},{"id":1741943,"name":"Patricia Rakopoulos","orcid":null,"position":3,"is_corresponding":false},{"id":1741944,"name":"Rahul Krishnatry","orcid":null,"position":4,"is_corresponding":false},{"id":899512,"name":"Mary Shago","orcid":"0000-0002-7386-2504","position":5,"is_corresponding":false},{"id":1741945,"name":"James Stavropoulos","orcid":null,"position":6,"is_corresponding":false},{"id":34228,"name":"Noa Alon","orcid":"0000-0001-9483-1785","position":7,"is_corresponding":false},{"id":792973,"name":"Jason D. Pole","orcid":"0000-0002-0413-5434","position":8,"is_corresponding":false},{"id":177736,"name":"Peter N. Ray","orcid":null,"position":9,"is_corresponding":false},{"id":1741946,"name":"Vilma Navickiene","orcid":null,"position":10,"is_corresponding":false},{"id":1741947,"name":"Joshua Mangerel","orcid":null,"position":11,"is_corresponding":false},{"id":607807,"name":"Marc Remke","orcid":"0000-0002-9404-9993","position":12,"is_corresponding":false},{"id":1741948,"name":"Pawel Buczkowicz","orcid":null,"position":13,"is_corresponding":false},{"id":132005,"name":"Vijay Ramaswamy","orcid":null,"position":14,"is_corresponding":false},{"id":1741949,"name":"Ana Guerreiro Stucklin","orcid":null,"position":15,"is_corresponding":false},{"id":1741950,"name":"Martin Li","orcid":null,"position":16,"is_corresponding":false},{"id":721687,"name":"Edwin J. Young","orcid":"0000-0003-4882-6752","position":17,"is_corresponding":false},{"id":781395,"name":"Cindy Zhang","orcid":"0000-0002-0243-7842","position":18,"is_corresponding":false},{"id":1741951,"name":"Pedro Castelo-Branco","orcid":null,"position":19,"is_corresponding":false},{"id":1741952,"name":"Doua Bakry","orcid":null,"position":20,"is_corresponding":false},{"id":457577,"name":"Suzanne Laughlin","orcid":"0000-0002-9972-5858","position":21,"is_corresponding":false},{"id":393472,"name":"Adam Shlien","orcid":"0000-0002-0368-5370","position":22,"is_corresponding":false},{"id":1741957,"name":"Jennifer Chan","orcid":null,"position":23,"is_corresponding":false},{"id":1412,"name":"Keith L. Ligon","orcid":"0000-0002-7733-600X","position":24,"is_corresponding":false},{"id":607800,"name":"James T. Rutka","orcid":"0000-0003-0851-7330","position":25,"is_corresponding":false},{"id":73394,"name":"Peter B. Dirks","orcid":"0000-0001-5718-6465","position":26,"is_corresponding":false},{"id":58302,"name":"Michael D. Taylor","orcid":"0000-0001-8136-5359","position":27,"is_corresponding":false},{"id":1741962,"name":"Mark Greenberg","orcid":null,"position":28,"is_corresponding":false},{"id":247632,"name":"David Malkin","orcid":"0000-0001-5752-9763","position":29,"is_corresponding":false},{"id":1190440,"name":"Annie Huang","orcid":"0009-0008-8397-4922","position":30,"is_corresponding":false},{"id":1620328,"name":"Eric Bouffet","orcid":null,"position":31,"is_corresponding":false},{"id":1741963,"name":"Cynthia E. Hawkins","orcid":null,"position":32,"is_corresponding":false},{"id":240510,"name":"Uri Tabori","orcid":"0000-0002-5019-2683","position":33,"is_corresponding":false},{"id":1741941,"name":"Matthew Mistry","orcid":null,"position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"<i>BRAF</i> Mutation and <i>CDKN2A</i> Deletion Define a Clinically Distinct Subgroup of Childhood Secondary High-Grade Glioma","abstract":"PURPOSE: To uncover the genetic events leading to transformation of pediatric low-grade glioma (PLGG) to secondary high-grade glioma (sHGG). PATIENTS AND METHODS: We retrospectively identified patients with sHGG from a population-based cohort of 886 patients with PLGG with long clinical follow-up. Exome sequencing and array CGH were performed on available samples followed by detailed genetic analysis of the entire sHGG cohort. Clinical and outcome data of genetically distinct subgroups were obtained. RESULTS: sHGG was observed in 2.9% of PLGGs (26 of 886 patients). Patients with sHGG had a high frequency of nonsilent somatic mutations compared with patients with primary pediatric high-grade glioma (HGG; median, 25 mutations per exome; P = .0042). Alterations in chromatin-modifying genes and telomere-maintenance pathways were commonly observed, whereas no sHGG harbored the BRAF-KIAA1549 fusion. The most recurrent alterations were BRAF V600E and CDKN2A deletion in 39% and 57% of sHGGs, respectively. Importantly, all BRAF V600E and 80% of CDKN2A alterations could be traced back to their PLGG counterparts. BRAF V600E distinguished sHGG from primary HGG (P = .0023), whereas BRAF and CDKN2A alterations were less commonly observed in PLGG that did not transform (P < .001 and P < .001 respectively). PLGGs with BRAF mutations had longer latency to transformation than wild-type PLGG (median, 6.65 years [range, 3.5 to 20.3 years] v 1.59 years [range, 0.32 to 15.9 years], respectively; P = .0389). Furthermore, 5-year overall survival was 75% ± 15% and 29% ± 12% for children with BRAF mutant and wild-type tumors, respectively (P = .024). CONCLUSION: BRAF V600E mutations and CDKN2A deletions constitute a clinically distinct subtype of sHGG. The prolonged course to transformation for BRAF V600E PLGGs provides an opportunity for surgical interventions, surveillance, and targeted therapies to mitigate the outcome of sHGG.","is_dataset_classified":null,"base_score":5.662960480135946,"endowment":5.662960480135946,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"25667294","pmcid":"PMC4356711","openalex_id":"https://openalex.org/W2115078134","authors":[],"funders":[{"funder_name":"NCI NIH HHS","grant_id":"P01 CA142536","title":null},{"funder_name":"Canadian Institutes of Health Research","grant_id":"MOP-123268","title":null}],"total_grants":2,"fwci":16.1475,"citation_percentile":0.99408111,"influential_citations":0,"citation_trend":[{"year":2015,"count":16},{"year":2016,"count":20},{"year":2017,"count":34},{"year":2018,"count":30},{"year":2019,"count":32},{"year":2020,"count":34},{"year":2021,"count":29},{"year":2022,"count":17},{"year":2023,"count":19},{"year":2024,"count":30},{"year":2025,"count":17},{"year":2026,"count":9}],"oa_status":"bronze","license":"cc-by","oa_locations":[{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2014.58.3922","host_type":"journal"},{"url":"https://ascopubs.org/doi/pdfdirect/10.1200/JCO.2014.58.3922","host_type":"publisher"},{"url":"https://doi.org/10.1200/jco.2014.58.3922","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/25667294","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/4356711","host_type":"repository"},{"url":"http://hdl.handle.net/10400.1/11546","host_type":"repository"}],"fields_of_study":["Glioma Diagnosis and Treatment","Neurofibromatosis and Schwannoma Cases","Meningioma and schwannoma management","Adolescent","Brain Neoplasms","Cell Transformation, Neoplastic","Child","Child, Preschool","Chromatin","Cyclin-Dependent Kinase Inhibitor p16","Disease Progression","Female","Follow-Up Studies","Gene Deletion","Glioma","Humans","Infant","Male","Mutation","Point Mutation","Proto-Oncogene Proteins B-raf","Retrospective Studies","Telomere","Treatment Outcome"],"mesh_terms":["Adolescent","Brain Neoplasms","Cell Transformation, Neoplastic","Child","Child, Preschool","Chromatin","Female","Follow-Up Studies","Glioma","Humans","Infant","Male","Mutation","Retrospective Studies","Telomere","Treatment Outcome","Gene Deletion","Point Mutation","Disease Progression","Cyclin-Dependent Kinase Inhibitor p16","Proto-Oncogene Proteins B-raf"],"keywords":["CDKN2A","Medicine","Glioma","V600E","Oncology","Cancer research","Exome sequencing","Internal medicine","Mutation","Biology","Gene","Genetics","Cancer"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"doi"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-13T16:23:53.829305Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}