Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma
Recommended Citation
Gielniewski B, Poleszak K, Roura AJ, Szadkowska P, Jacek K, Krol SK, Guzik R, Wiechecka P, Maleszewska M, Kaza B, Marchel A, Czernicki T, Koziarski A, Zielinski G, Styk A, Kawecki M, Szczylik C, Czepko R, Banach M, Kaspera W, Szopa W, Bujko M, Czapski B, Zabek M, Iżycka-Świeszewska E, Kloc W, Nauman P, Cieslewicz J, Grajkowska W, Morosini N, Noushmehr H, Wojtas B, and Kaminska B. Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma. Int J Cancer 2023.
Document Type
Article
Publication Date
9-1-2023
Publication Title
International journal of cancer
Abstract
High-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.
Medical Subject Headings
Humans; Glioblastoma; Brain Neoplasms; Glioma; Prognosis; DNA; Isocitrate Dehydrogenase; Mutation
PubMed ID
37338006
ePublication
ePub ahead of print
Volume
153
Issue
5
First Page
1003
Last Page
1015
