Research Papers:

Treatment-associated TP53 DNA-binding domain missense mutations in the pathogenesis of secondary gliosarcoma

Margaret Pain, Huaien Wang, Eunjee Lee, Maya Strahl, Wissam Hamou, Robert Sebra, Jun Zhu and Raymund L. Yong _

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Oncotarget. 2018; 9:2603-2621. https://doi.org/10.18632/oncotarget.23517

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Margaret Pain1,*, Huaien Wang1,*, Eunjee Lee2, Maya Strahl2, Wissam Hamou2, Robert Sebra2, Jun Zhu2 and Raymund L. Yong1

1Departments of Neurosurgery and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

2Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

*These authors have contributed equally to this work

Correspondence to:

Raymund L. Yong, email: [email protected]

Keywords: glioblastoma; gliosarcoma; TP53 mutation; temozolomide; mutagenesis

Received: October 11, 2017     Accepted: December 11, 2017     Published: December 20, 2017


Background: Gliosarcoma is a rare variant of glioblastoma (GBM) that exhibits frequent mutations in TP53 and can develop in a secondary fashion after chemoradiation of a primary GBM. Whether temozolomide (TMZ)-induced mutagenesis of the TP53 DNA-binding domain (DBD) can drive the pathogenesis of gliosarcoma is unclear.

Methods: We identified a case of a primary GBM that rapidly progressed into secondary gliosarcoma shortly after chemoradiation was initiated. Bulk tumor was collected and gliomasphere cultures derived from both the pre- and post-treatment tumors. We performed targeted DNA sequencing and transcriptome analyses of the specimens to understand their phylogenetic relationship and identify differentially expressed gene pathways. Gliomaspheres from the primary GBM were treated with TMZ and then analyzed to compare patterns of mutagenesis in vivo and ex vivo.

Results: The pre- and post-treatment tumors shared EGFR, CDKN2A, and PTEN mutations, but only the secondary gliosarcoma exhibited TP53 DBD missense mutations. Two mutations, R110C, and R175H, were identified, each in distinct clones. Both were base transitions characteristic of TMZ mutagenesis. Gene expression analysis identified increased JAK-STAT signaling in the gliosarcoma, together with reduced expression of microRNAs known to regulate epithelial-mesenchymal transition. Ex vivo treatment of the GBM spheres with TMZ generated numerous variants in cancer driver genes, including TP53 and CDH1, which were mutated in the post-treatment tumor.

Conclusions: TMZ-induced TP53 gain-of-function mutations can have a driving role in secondary gliosarcoma pathogenesis. Analysis of variants identified in ex vivo TMZ-treated gliomaspheres may have utility in predicting GBM evolutionary trajectories in vivo during standard chemoradiation.

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