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Published on: March 31, 2015
Out-of-frame CBX3::ALK fusion drives ALK activation and therapy response
Jen-Fan Hang1, Han-Ying Cheng2, Yu-Shuen Tsai3
1Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan; Department of Pathology, School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
Abstract:
Kinase gene fusions are critical oncogenic drivers and key targets in precision oncology. Here, we report a CBX3::ALK out-of-frame fusion identified in a case of metastatic melanoma, which produces functional ALK isoforms via alternative translation start sites. The patient demonstrates a remarkable clinical response to the ALK inhibitor alectinib. Functional studies confirm that the CBX3::ALK-derived isoforms retain oncogenic signaling and tumorigenic potential. Our findings reveal limitations in current tertiary analysis strategies for functional gene fusion detection that may overlook clinically relevant out-of-frame fusions. Additional analysis of pan-cancer RNA sequencing data from 5,725 tumors and genomic datasets comprising 6,977 melanomas demonstrates that such events are rare but potentially significant. This study highlights the need to consider alternative translation mechanisms and incorporate additional analytic filters, such as 5'/3' expression imbalance, to better capture actionable out-of-frame fusion events in the era of precision oncology.
Insights
A novel CBX3::ALK gene fusion in melanoma drives cancer and responds to targeted therapy. This discovery highlights the need for advanced detection methods for rare, actionable gene fusions in precision oncology.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Kinase gene fusions are crucial drivers of cancer and targets for precision oncology.
- Detecting functional gene fusions is essential for effective cancer treatment.
Purpose of the Study:
- To report a novel out-of-frame CBX3::ALK gene fusion in metastatic melanoma.
- To investigate the oncogenic potential and therapeutic implications of this fusion.
- To highlight limitations in current gene fusion detection strategies.
Main Methods:
- Identification of a CBX3::ALK out-of-frame fusion in a melanoma patient.
- Functional studies to assess oncogenic signaling and tumorigenic potential of fusion isoforms.
- Analysis of pan-cancer RNA sequencing and melanoma genomic datasets.
Main Results:
- The CBX3::ALK fusion produces functional ALK isoforms via alternative translation start sites.
- The patient showed a significant clinical response to the ALK inhibitor alectinib.
- Out-of-frame fusions are rare but potentially significant in cancer.
Conclusions:
- Current tertiary analysis may miss clinically relevant out-of-frame fusions.
- Alternative translation mechanisms and analytic filters (e.g., 5'/3' expression imbalance) are needed for comprehensive fusion detection.
- This finding emphasizes the importance of exploring novel fusion events in precision oncology.
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