Targeted sequencing of cancer‐related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma

Author:

Gielniewski Bartlomiej1,Poleszak Katarzyna1,Roura Adria‐Jaume1,Szadkowska Paulina1,Jacek Karol1,Krol Sylwia K.1,Guzik Rafal1,Wiechecka Paulina1,Maleszewska Marta1,Kaza Beata1,Marchel Andrzej2,Czernicki Tomasz2,Koziarski Andrzej3,Zielinski Grzegorz3,Styk Andrzej3,Kawecki Maciej45,Szczylik Cezary4,Czepko Ryszard6,Banach Mariusz6,Kaspera Wojciech7,Szopa Wojciech7,Bujko Mateusz5,Czapski Bartosz8,Zabek Miroslaw89,Iżycka‐Świeszewska Ewa10,Kloc Wojciech1112,Nauman Pawel1314,Cieslewicz Joanna15,Grajkowska Wieslawa16,Morosini Natalia17,Noushmehr Houtan17,Wojtas Bartosz1ORCID,Kaminska Bozena1

Affiliation:

1. Laboratory of Molecular Neurobiology Nencki Institute of Experimental Biology of the Polish Academy of Sciences Warsaw Poland

2. Department of Neurosurgery Medical University of Warsaw Warsaw Poland

3. Department of Neurosurgery Military Institute of Medicine Warsaw Poland

4. Department of Oncology Military Institute of Medicine Warsaw Poland

5. The Maria Sklodowska‐Curie National Research Institute of Oncology Warsaw Poland

6. Department of Neurosurgery Andrzej Frycz Modrzewski Krakow University Krakow Poland

7. Department of Neurosurgery Medical University of Silesia, Regional Hospital Sosnowiec Poland

8. Department of Neurosurgery Mazovian Brodnowski Hospital Warsaw Poland

9. Department of Neurosurgery and Nervous System Trauma Centre of Postgraduate Medical Education Warsaw Poland

10. Medical University of Gdansk Gdansk Poland

11. Department of Neurosurgery Copernicus PL Gdansk Poland

12. Department of Psychology and Sociology of Health and Public Health School of Public Health Collegium Medicum University of Warmia – Mazury Olsztyn Poland

13. Institute of Psychiatry and Neurology Warsaw Poland

14. Faculty of Medical and Health Sciences Siedlce University of Natural Sciences and Humanities Siedlce Poland

15. Gdansk University of Technology, Faculty of Chemistry Gdansk Poland

16. Department of Pathology The Children's Memorial Health Institute Warsaw Poland

17. Department of Neurosurgery Henry Ford Cancer Institute Detroit Michigan USA

Abstract

AbstractHigh‐grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next‐generation sequencing with a custom panel of 664 cancer‐ and epigenetics‐related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH‐wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high‐grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH‐wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology.

Funder

Fundacja na rzecz Nauki Polskiej

Publisher

Wiley

Subject

Cancer Research,Oncology

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