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Published on: June 4, 2017
Fusion transcriptome landscape in glioblastoma: Incidence and therapeutic implications
Sonikpreet Aulakh1, Joanne Xiu2, Shawn Kothari3
1Department of Medical Oncology, West Virginia University, Morgantown.
Background:
Glioblastoma (GBM) lacks effective therapies for recurrent disease. Unlike cancers with successful fusion-targeted treatments (eg BCR-ABL1 in CML), the incidence and therapeutic potential of gene fusions in GBM remain unclear. We analyzed a large genomic database to define fusion frequency and molecular associations.
Methods:
4800 IDH-wildtype GBM samples (WHO 2021) underwent NextGen DNA sequencing (592-gene panel/whole exome) and Whole Transcriptome Sequencing for fusions at Caris Life Sciences. Fisher-Exact/Chi-Square tests, adjusted by Benjamini-Hochberg (q < 0.05), assessed significance.
Results:
Pathogenic fusions occurred in 428 (8.9%) samples, primarily FGFR3 (37%, n = 159; FGFR3: TACC3, n = 134), MET (21%, n = 92), and EGFR (20%, n = 87). Pathogenic or likely pathogenic fusions included NTRK2 (n = 27), PDGFRA (n = 23), ROS1 (n = 14), and BRAF (n = 10). Fusion-positive tumors had higher MET (7.5% vs. 0.7%), FGFR3 (5% vs. 0.2%), CDK4 (17% vs. 11%), and MDM2 (12% vs. 7.5%) amplifications, but lower EGFR mutations (6.1% vs. 18%), amplifications (6.1% vs. 18%), and EGFRvIII (11.9% vs. 22.5%) (all q < 0.05). Median survival was 16.6 months (fusion-positive) vs. 15.5 months (fusion-negative) (P = 0.043). Tyrosine kinase inhibitor (TKI)-treated fusion-positive patients (n = 37) showed no significant survival benefit (18.4 vs. 16.5 months, P = .971).
Conclusions:
Approximately 9% of GBMs harbor targetable fusions, with five genes (FGFR3, MET, EGFR, NTRK2, PDGFRA) comprising 8%. These findings support multi-arm clinical trials to evaluate targeted therapies, potentially improving outcomes for molecularly defined GBM subgroups.
Insights
Approximately 9% of glioblastoma (GBM) cases harbor targetable gene fusions, primarily involving FGFR3, MET, and EGFR. These findings suggest potential for targeted therapies in specific GBM molecular subgroups.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Glioblastoma (GBM) presents a significant challenge due to a lack of effective therapies for recurrent disease.
- The incidence and therapeutic relevance of gene fusions in GBM are not well-established, unlike in other cancers with successful fusion-targeted treatments.
Purpose of the Study:
- To determine the frequency of gene fusions in a large cohort of glioblastoma.
- To identify molecular associations and potential therapeutic targets within GBM based on fusion status.
Main Methods:
- Analysis of Next-Generation DNA sequencing and Whole Transcriptome Sequencing data from 4800 IDH-wildtype GBM samples.
- Statistical analysis using Fisher-Exact and Chi-Square tests, with Benjamini-Hochberg adjustment for significance (q < 0.05).
Main Results:
- Pathogenic gene fusions were identified in 8.9% of GBM samples, with FGFR3, MET, and EGFR being the most prevalent.
- Fusion-positive GBMs showed distinct amplification and mutation profiles compared to fusion-negative tumors.
- Median survival was slightly improved in fusion-positive patients (16.6 months) versus fusion-negative (15.5 months), though tyrosine kinase inhibitor (TKI) treatment did not yield a significant survival benefit.
Conclusions:
- Approximately 9% of GBMs harbor targetable fusions, with FGFR3, MET, EGFR, NTRK2, and PDGFRA being key genes.
- These findings support the development of multi-arm clinical trials to investigate targeted therapies for molecularly defined GBM subgroups.
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