Débora Cabral de Carvalho Corrêa1,2, Francine Tesser-Gamba1, Indhira Dias Oliveira1, Nasjla Saba da Silva1, Andrea Maria Capellano1, Maria Teresa de Seixas Alves1,3, Patrícia Alessandra Dastoli1,4, Sergio Cavalheiro1,4, Silvia Regina Caminada de Toledo5,6. 1. Department of Pediatrics, Pediatric Oncology Institute-GRAACC/UNIFESP, Federal University of Sao Paulo, 743 Botucatu Street, 8th Floor - Genetics Laboratory, Vila Clementino, Sao Paulo, SP, 04023-062, Brazil. 2. Division of Genetics, Department of Morphology and Genetics, Federal University of Sao Paulo, Sao Paulo, SP, Brazil. 3. Department of Pathology, Federal University of Sao Paulo, Sao Paulo, SP, Brazil. 4. Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo, SP, Brazil. 5. Department of Pediatrics, Pediatric Oncology Institute-GRAACC/UNIFESP, Federal University of Sao Paulo, 743 Botucatu Street, 8th Floor - Genetics Laboratory, Vila Clementino, Sao Paulo, SP, 04023-062, Brazil. silviatoledo@graacc.org.br. 6. Division of Genetics, Department of Morphology and Genetics, Federal University of Sao Paulo, Sao Paulo, SP, Brazil. silviatoledo@graacc.org.br.
Abstract
PURPOSE: 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. METHODS: 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, from Thermo Fisher Scientific®. RESULTS: 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. CONCLUSION: 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.
PURPOSE: 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. METHODS: 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, from Thermo Fisher Scientific®. RESULTS: 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. CONCLUSION: 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.
Authors: Leomar Y Ballester; Jeanne M Meis; Alexander J Lazar; Sujit S Prabhu; Kimberly B Hoang; Norman E Leeds; Gregory N Fuller Journal: J Neuropathol Exp Neurol Date: 2020-03-01 Impact factor: 3.685
Authors: Anastasia Drobysheva; Laura J Klesse; Daniel C Bowers; Veena Rajaram; Dinesh Rakheja; Charles F Timmons; Jason Wang; Korgun Koral; Lynn Gargan; Erica Ramos; Jason Y Park Journal: J Natl Compr Canc Netw Date: 2017-08 Impact factor: 11.908
Authors: Azadeh Ebrahimi; Marco Skardelly; Martin U Schuhmann; Martin Ebinger; David Reuss; Manuela Neumann; Ghazaleh Tabatabai; Patricia Kohlhof-Meinecke; Jens Schittenhelm Journal: J Cancer Res Clin Oncol Date: 2019-01-04 Impact factor: 4.553
Authors: Matthew Clarke; Alan Mackay; Britta Ismer; Jessica C Pickles; Ruth G Tatevossian; Scott Newman; Tejus A Bale; Iris Stoler; Elisa Izquierdo; Sara Temelso; Diana M Carvalho; Valeria Molinari; Anna Burford; Louise Howell; Alex Virasami; Amy R Fairchild; Aimee Avery; Jane Chalker; Mark Kristiansen; Kelly Haupfear; James D Dalton; Wilda Orisme; Ji Wen; Michael Hubank; Kathreena M Kurian; Catherine Rowe; Mellissa Maybury; Stephen Crosier; Jeffrey Knipstein; Ulrich Schüller; Uwe Kordes; David E Kram; Matija Snuderl; Leslie Bridges; Andrew J Martin; Lawrence J Doey; Safa Al-Sarraj; Christopher Chandler; Bassel Zebian; Claire Cairns; Rachael Natrajan; Jessica K R Boult; Simon P Robinson; Martin Sill; Ira J Dunkel; Stephen W Gilheeney; Marc K Rosenblum; Debbie Hughes; Paula Z Proszek; Tobey J Macdonald; Matthias Preusser; Christine Haberler; Irene Slavc; Roger Packer; Ho-Keung Ng; Shani Caspi; Mara Popović; Barbara Faganel Kotnik; Matthew D Wood; Lissa Baird; Monika Ashok Davare; David A Solomon; Thale Kristin Olsen; Petter Brandal; Michael Farrell; Jane B Cryan; Michael Capra; Michael Karremann; Jens Schittenhelm; Martin U Schuhmann; Martin Ebinger; Winand N M Dinjens; Kornelius Kerl; Simone Hettmer; Torsten Pietsch; Felipe Andreiuolo; Pablo Hernáiz Driever; Andrey Korshunov; Lotte Hiddingh; Barbara C Worst; Dominik Sturm; Marc Zuckermann; Olaf Witt; Tabitha Bloom; Clare Mitchell; Evelina Miele; Giovanna Stefania Colafati; Francesca Diomedi-Camassei; Simon Bailey; Andrew S Moore; Timothy E G Hassall; Stephen P Lowis; Maria Tsoli; Mark J Cowley; David S Ziegler; Matthias A Karajannis; Kristian Aquilina; Darren R Hargrave; Fernando Carceller; Lynley V Marshall; Andreas von Deimling; Christof M Kramm; Stefan M Pfister; Felix Sahm; Suzanne J Baker; Angela Mastronuzzi; Andrea Carai; Maria Vinci; David Capper; Sergey Popov; David W Ellison; Thomas S Jacques; David T W Jones; Chris Jones Journal: Cancer Discov Date: 2020-04-01 Impact factor: 39.397