RT Journal Article SR Electronic T1 The novel, recurrent mutation in the TOP2A gene results in the enhanced topoisomerase activity and transcription deregulation in glioblastoma JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.06.17.158477 DO 10.1101/2020.06.17.158477 A1 Bartlomiej Gielniewski A1 Katarzyna Poleszak A1 Adria-Jaume Roura A1 Paulina Szadkowska A1 Sylwia K. Krol A1 Rafal Guzik A1 Paulina Wiechecka A1 Marta Maleszewska A1 Beata Kaza A1 Andrzej Marchel A1 Tomasz Czernicki A1 Andrzej Koziarski A1 Grzegorz Zielinski A1 Andrzej Styk A1 Maciej Kawecki A1 Cezary Szczylik A1 Ryszard Czepko A1 Mariusz Banach A1 Wojciech Kaspera A1 Wojciech Szopa A1 Mateusz Bujko A1 Bartosz Czapski A1 Miroslaw Zabek A1 Ewa Izycka-Swieszewska A1 Wojciech Kloc A1 Pawel Nauman A1 Joanna Cieslewicz A1 Bartosz Wojtas A1 Bozena Kaminska YR 2021 UL http://biorxiv.org/content/early/2021/02/22/2020.06.17.158477.abstract AB Background High grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. We aim to better understand glioma pathobiology and find potential therapeutic susceptibilities.Methods We designed a custom panel of 664 cancer- and epigenetics-related genes, and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 gliomas of different malignancy grades. mRNA sequencing was performed to detect transcriptomic abnormalities.Results In addition to known alterations in TP53, IDH1, ATRX, EGFR genes found in this cohort, we identified a novel, recurrent mutation in the TOP2A gene coding for Topoisomerase 2A occurring only in glioblastomas (GBM, WHO grade IV gliomas). Biochemical assays with recombinant proteins demonstrated stronger DNA binding and DNA supercoil relaxation activities of the variant proteins. GBM patients carrying the mutated TOP2A had shorter overall survival than those with the wild type TOP2A. Computational analyses of transcriptomic data showed that GBMs with the mutated TOP2A have different transcriptomic patterns suggesting higher transcriptomic activity.Conclusion We identified a novel TOP2A E948Q variant that strongly binds to DNA and is more active than the wild type protein. Our findings suggest that the discovered TOP2A variant is gain–of-function mutation.Key pointsThe most frequent genetic alterations in high grade gliomas are reported.A new mutation in the TOP2A gene was found in 4 patients from Polish population.A E948Q substitution changes TOP2A activities towards DNA.The recurrent TOP2A variant is a gain-of-function mutation.Importance of the study Glioblastoma is a deadly disease. Despite recent advancements in genomics and innovative targeted therapies, glioblastoma therapy has not shown improvements. Insights into glioblastoma biology may improve diagnosis, prognosis, and treatment prediction, directing to a better outcome. We performed targeted sequencing of 664 cancer genes, and identified a new variant of the TOP2A gene encoding topoisomerase 2A in glioblastomas. The TOP2A protein variant shows a higher affinity towards DNA and causes transcriptional alterations, suggesting a higher de novo transcription rate.Competing Interest StatementThe authors have declared no competing interest.