Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors

Author:

Kashani Elham12ORCID,Schnidrig Désirée34,Gheinani Ali Hashemi567ORCID,Ninck Martina Selina1,Zens Philipp18,Maragkou Theoni1,Baumgartner Ulrich910ORCID,Schucht Philippe11,Rätsch Gunnar412ORCID,Rubin Mark A313,Benjak Andrej,Bruggmann Rémy,Comoglio Federico,Kahles André,Keller Irene,K Y Ng Charlotte,Piscuoglio Salvatore,Prélot Laurie,Rätsch Gunnar,A Rubin Mark,Schnidrig Désirée,Selimovic-Hamza Senija,Thomas Tinu M,Berezowska Sabina114,Ng Charlotte K Y3413ORCID,Vassella Erik1ORCID,

Affiliation:

1. Institute of Pathology, University of Bern , Bern , Switzerland

2. Graduate School for Cellular and Biomedical Sciences, University of Bern , Bern , Switzerland

3. Department for BioMedical Research, University of Bern , Bern , Switzerland

4. SIB Swiss Institute of Bioinformatics , Lausanne , Switzerland

5. Urological Diseases Research Center, Boston Children’s Hospital , Boston, MA , USA

6. Department of Surgery, Harvard Medical School , Boston, MA , USA

7. Broad Institute of MIT and Harvard , Cambridge, MA , USA

8. Graduate School for Health Sciences, University of Bern , Bern , Switzerland

9. Cell and Molecular Biology Department, QIMR Berghofer Medical Research Institute, Sid Faithfull Brain Cancer Laboratory , Brisbane , Australia

10. School of Biomedical Sciences, University of Queensland , Brisbane , Australia

11. Department of Neurosurgery, University Hospital Bern , Bern , Switzerland

12. ETH Zurich , Zurich , Switzerland

13. Bern Center for Precision Medicine , Bern , Switzerland

14. Institute of Pathology, Lausanne University Hospital and University of Lausanne , Lausanne , Switzerland

Abstract

Abstract Background Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge for therapeutic intervention. Methods In a single-center retrospective study of matched pairs of initial and post-therapeutic glioma cases with a recurrence period greater than 1 year, we performed whole exome sequencing combined with mRNA and microRNA expression profiling to identify processes that are altered in recurrent gliomas. Results Mutational analysis of recurrent gliomas revealed early branching evolution in 75% of the patients. High plasticity was confirmed at the mRNA and miRNA levels. SBS1 signature was reduced and SBS11 was elevated, demonstrating the effect of alkylating agent therapy on the mutational landscape. There was no evidence for secondary genomic alterations driving therapy resistance. ALK7/ACVR1C and LTBP1 were upregulated, whereas LEFTY2 was downregulated, pointing towards enhanced Tumor Growth Factor β (TGF-β) signaling in recurrent gliomas. Consistently, altered microRNA expression profiles pointed towards enhanced Nuclear Factor Kappa B and Wnt signaling that, cooperatively with TGF-β, induces epithelial to mesenchymal transition (EMT), migration, and stemness. TGF-β-induced expression of pro-apoptotic proteins and repression of antiapoptotic proteins were uncoupled in the recurrent tumor. Conclusions Our results suggest an important role of TGF-β signaling in recurrent gliomas. This may have clinical implications since TGF-β inhibitors have entered clinical phase studies and may potentially be used in combination therapy to interfere with chemoradiation resistance. Recurrent gliomas show high incidence of early branching evolution. High tumor plasticity is confirmed at the level of microRNA and mRNA expression profiles.

Funder

Swiss National Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Cancer Research,Neurology (clinical),Oncology

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