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

Kashani, Elham; Schnidrig, Désirée; Hashemi Gheinani, Ali; Ninck, Martina Selina; Zens, Philipp; Maragkou, Theoni; Baumgartner, Ulrich; Schucht, Philippe; Rätsch, Gunnar; Rubin, Mark A; Berezowska, Sabina; Ng, Charlotte K Y; Vassella, Erik (2022). Integrated longitudinal analysis of adult grade 4 diffuse gliomas with long-term relapse interval revealed upregulation of TGF-β signaling in recurrent tumors. (In Press). Neuro-Oncology Oxford University Press 10.1093/neuonc/noac220

Full text not available from this repository. (Request a copy)

BACKGROUND

Adult-type diffuse gliomas, CNS WHO grade 4 are the most aggressive primary brain tumors and represent a particular challenge of 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 one 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 seventy-five percent of 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 anti-apoptotic 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 implication, 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Service Sector > Institute of Pathology > Clinical Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Urologie

04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Department of Head Organs and Neurology (DKNS) > Clinic of Neurosurgery
04 Faculty of Medicine > Service Sector > Institute of Pathology > Tumour Pathology

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)
Graduate School for Health Sciences (GHS)

UniBE Contributor:

Kashani, Elham; Schnidrig, Désirée; Hashemi Gheinani, Ali; Ninck, Martina Selina; Zens, Philipp Immanuel; Maragkou, Theoni; Schucht, Philippe; Rubin, Mark Andrew; Berezowska, Sabina Anna; Ng, Kiu Yan Charlotte and Vassella, Erik

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1523-5866

Publisher:

Oxford University Press

Language:

English

Submitter:

Pubmed Import

Date Deposited:

21 Sep 2022 14:45

Last Modified:

05 Dec 2022 16:25

Publisher DOI:

10.1093/neuonc/noac220

PubMed ID:

36124685

Uncontrolled Keywords:

Glioblastoma TGF-β signaling longitudinal analysis miRNA tumor evolution

URI:

https://boris.unibe.ch/id/eprint/173104

Actions (login required)

Edit item Edit item
Provide Feedback