BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. METHODS: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. RESULTS: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. CONCLUSIONS: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

1st Department of Paediatrics Aghia Sophia Children's Hospital National and Kapodistrian University of Athens Athens Greece

2nd Department of Pediatrics Semmelweis University Budapest Hungary

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin HIT LOGGIC German Registry for children and adolescents with low grade glioma Berlin Germany

Children's Cancer Institute Lowy Cancer Research Centre UNSW Sydney Sydney Australia

Clinical Cooperation Unit Neuropathology German Cancer Research Center Heidelberg Germany

Clinical Cooperation Unit Pediatric Oncology German Cancer Research Center Heidelberg Germany

Department of Haematology and Oncology Children's Health Ireland at Crumlin Dublin Ireland

Department of Haematology and Oncology University Children's Hospital University Medical Centre Ljubljana Ljubljana Slovenia

Department of Health Sciences and Medicine University of Lucerne Lucerne Switzerland

Department of Neuropathology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Neuropathology Institute of Pathology Heidelberg University Hospital Heidelberg Germany

Department of Paediatrics and Adolescent Medicine The University Hospital Rigshospitalet Copenhagen Denmark

Department of Paediatrics McMaster Children's Hospital and McMaster University Hamilton Canada

Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine University Hospital Motol Charles University Prague Czech Republic

Department of Pediatric Hematology and Oncology Saint Luc University Hospital Brussels Belgium

Department of Pediatric Oncology Hematology Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin and Humboldt Universität zu Berlin Berlin Germany

Department of Pediatric Oncology Hematology Immunology and Pulmonology Heidelberg University Hospital Heidelberg Germany

Department of Pediatric Oncology Princess Máxima Center for Pediatric Oncology Utrecht Netherlands

Division of Neonatology Pediatric Intensive Care and Neuropediatrics Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Division of Pediatric Glioma Research German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Division of Pediatric Oncology Hematology Department of Pediatrics Kantonsspital Aarau Aarau Switzerland

German Cancer Consortium

German Cancer Consortium Heidelberg Germany

Great Ormond Street Hospital for Children NHS Trust London London UK

Heidelberg Medical Faculty University of Heidelberg Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Heidelberg Germany

Kids Cancer Centre Sydney Children's Hospital High St Randwick NSW Australia

National Center for Tumor Diseases Heidelberg Germany

Neuro Oncology Unit Pediatric Cancer Center Hospital Sant Joan de Deu Barcelona Spain

Pediatric Oncology Unit Padova University Padova Italy

School of Clinical Medicine UNSW Medicine and Health UNSW Sydney Sydney NSW Australia

Section of Pediatric Oncology UNN University Hospital of Northern Norway Tromsø Norway

Swedish Childhood Cancer Registry Karolinska Institutet Stockholm Sweden

Turku University and University Hospital Turku Finland

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$a BACKGROUND: The international, multicenter registry LOGGIC Core BioClinical Data Bank aims to enhance the understanding of tumor biology in pediatric low-grade glioma (pLGG) and provide clinical and molecular data to support treatment decisions and interventional trial participation. Hence, the question arises whether implementation of RNA sequencing (RNA-Seq) using fresh frozen (FrFr) tumor tissue in addition to gene panel and DNA methylation analysis improves diagnostic accuracy and provides additional clinical benefit. METHODS: Analysis of patients aged 0 to 21 years, enrolled in Germany between April 2019 and February 2021, and for whom FrFr tissue was available. Central reference histopathology, immunohistochemistry, 850k DNA methylation analysis, gene panel sequencing, and RNA-Seq were performed. RESULTS: FrFr tissue was available in 178/379 enrolled cases. RNA-Seq was performed on 125 of these samples. We confirmed KIAA1549::BRAF-fusion (n = 71), BRAF V600E-mutation (n = 12), and alterations in FGFR1 (n = 14) as the most frequent alterations, among other common molecular drivers (n = 12). N = 16 cases (13%) presented rare gene fusions (eg, TPM3::NTRK1, EWSR1::VGLL1, SH3PXD2A::HTRA1, PDGFB::LRP1, GOPC::ROS1). In n = 27 cases (22%), RNA-Seq detected a driver alteration not otherwise identified (22/27 actionable). The rate of driver alteration detection was hereby increased from 75% to 97%. Furthermore, FGFR1 internal tandem duplications (n = 6) were only detected by RNA-Seq using current bioinformatics pipelines, leading to a change in analysis protocols. CONCLUSIONS: The addition of RNA-Seq to current diagnostic methods improves diagnostic accuracy, making precision oncology treatments (MEKi/RAFi/ERKi/NTRKi/FGFRi/ROSi) more accessible. We propose to include RNA-Seq as part of routine diagnostics for all pLGG patients, especially when no common pLGG alteration was identified.

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