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Recurrent SPECC1L-NTRK fusions in pediatric sarcoma and brain tumors
Dong-Anh Khuong-Quang1,2,3, Lauren M Brown1,3,4, Marie Wong1,5
1Children's Cancer Institute, University of New South Wales, Randwick, 2031, Australia.
Abstract:
The identification of rearrangements driving expression of neurotrophic receptor tyrosine kinase (NTRK) family kinases in tumors has become critically important because of the availability of effective, specific inhibitor drugs. Whole-genome sequencing (WGS) combined with RNA sequencing (RNA-seq) can identify novel and recurrent expressed fusions. Here we describe three SPECC1L-NTRK fusions identified in two pediatric central nervous system cancers and an extracranial solid tumor using WGS and RNA-seq. These fusions arose either through a simple balanced rearrangement or in the context of a complex chromoplexy event. We cloned the SPECC1L-NTRK2 fusion directly from a patient sample and showed that enforced expression of this fusion is sufficient to promote cytokine-independent survival and proliferation. Cells transformed by SPECC1L-NTRK2 expression are sensitive to a TRK inhibitor drug. We report here that SPECC1L-NTRK fusions can arise in a range of pediatric cancers. Although WGS and RNA-seq are not required to detect NTRK fusions, these techniques may be of benefit when NTRK fusions are not suspected on clinical grounds or not identified by other methods.
Insights
Three novel SPECC1L-NTRK fusions were identified in pediatric cancers using whole-genome and RNA sequencing. These fusions drive tumor growth and are sensitive to TRK inhibitor drugs.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neurotrophic receptor tyrosine kinase (NTRK) fusions are critical drivers in various cancers, making them targets for specific inhibitor drugs.
- Identifying novel NTRK fusions is essential for expanding targeted therapy options.
Purpose of the Study:
- To identify and characterize novel SPECC1L-NTRK fusions in pediatric cancers.
- To investigate the oncogenic potential and therapeutic sensitivity of these fusions.
Main Methods:
- Whole-genome sequencing (WGS) and RNA sequencing (RNA-seq) were employed to detect gene fusions.
- Functional studies involved cloning and enforcing expression of the SPECC1L-NTRK2 fusion in cells.
- Sensitivity to TRK inhibitor drugs was assessed.
Main Results:
- Three SPECC1L-NTRK fusions were identified in two pediatric central nervous system cancers and one extracranial solid tumor.
- These fusions were found to arise from simple or complex genomic rearrangements.
- Enforced expression of SPECC1L-NTRK2 promoted cytokine-independent survival and proliferation, and transformed cells were sensitive to TRK inhibitors.
Conclusions:
- SPECC1L-NTRK fusions represent a newly identified class of oncogenic drivers in pediatric cancers.
- These findings highlight the potential of TRK inhibitors for treating tumors harboring SPECC1L-NTRK fusions.
- WGS and RNA-seq can detect NTRK fusions missed by other methods, especially when not clinically suspected.
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