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Published on: October 4, 2019
Small-RNA Profiling Links 5'-tRNA Halves to Post-therapeutic Disease Persistence and Poor Patient Survival in
Abstract:
Glioblastoma (GBM) is a highly lethal brain cancer with limited therapeutic durability, where the majority of patients develop recurrent or persistent disease after standard chemoradiotherapy. Meanwhile, tRNA-derived fragments (tRFs) have become increasingly relevant to cancer biology; however, their clinical relevance in GBM remains undefined. Here, we report that a specific family of tRFs, 5'-tRNA halves (tiR5s) dominates the small RNA landscape of GBM patient tumors and associates with worse overall survival, post-therapeutic disease persistence, and pro-invasive proteogenomic pathways across two independent GBM patient cohorts. This association between elevated tiR5 levels and therapeutic resistance re-emerges in radiation-resistant GBM xenograft models. Our findings reveal that tiR5s are an underappreciated molecular feature of highly aggressive GBM tumors, supporting further investigation into their biological roles and prognostic utility in GBM.
Highlights:
tiR5s are the predominant tRF family in primary GBM patient tumorsElevated tiR5 expression distinguishes primary GBM tumors that develop persistent disease after first-line therapyRadiation-resistant GBM PDX models show elevated tiR5 expressionElevated tiR5 expression associates with poor overall patient survival and pro-invasive molecular programs in GBM patient tumors.
Insights
Specific tRNA fragments called 5'-tRNA halves (tiR5s) are dominant in glioblastoma (GBM) tumors. Elevated tiR5 levels correlate with poor survival and treatment resistance in GBM patients, suggesting prognostic utility.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Glioblastoma (GBM) is an aggressive brain cancer with poor therapeutic outcomes.
- Limited understanding exists regarding the clinical relevance of tRNA-derived fragments (tRFs) in GBM.
- The prognostic and predictive value of specific tRFs in GBM remains largely undefined.
Purpose of the Study:
- To investigate the clinical significance of tRNA-derived fragments (tRFs) in glioblastoma (GBM).
- To determine the association between specific tRFs and patient survival, therapeutic resistance, and tumor invasiveness in GBM.
- To explore the potential of tRFs as biomarkers for GBM aggressiveness.
Main Methods:
- Analysis of small RNA sequencing data from GBM patient tumors and xenograft models.
- Correlation of tRF expression levels with clinical outcomes, including overall survival and treatment response.
- Proteogenomic pathway analysis to identify molecular mechanisms associated with tRF expression.
Main Results:
- A specific family of tRFs, 5 -tRNA halves (tiR5s), predominates in GBM tumors.
- Elevated tiR5 expression is associated with worse overall survival and persistent disease post-therapy in GBM patients.
- Increased tiR5 levels were observed in radiation-resistant GBM models and linked to pro-invasive molecular programs.
Conclusions:
- 5 -tRNA halves (tiR5s) are a significant molecular feature of aggressive GBM.
- tiR5s show potential as prognostic biomarkers for GBM patient survival and therapeutic resistance.
- Further research into the biological functions of tiR5s in GBM is warranted.
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