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| Status |
Public on Apr 29, 2024 |
| Title |
Genome-wide identification of oncogenic fusions in lung cancer by functional translocation sequencing |
| Organism |
Homo sapiens |
| Experiment type |
Other
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| Summary |
Fusions involving tyrosine kinases are oncogenic drivers in lung cancer and other solid tumors but also mediate resistance to targeted therapy. Despite gene rearrangements involving tyrosine kinases tending to show recurrent patterns in solid tumors, little is known about their mechanisms of formation and their selection process. To elucidate these mechanisms, we developed a functional high-throughput, genome-wide translocation sequencing (F-HTGTS) approach. We applied F-HTGTS to lung cancer cells under the selective pressure of EGFR inhibition to map genome-wide translocations when a DNA double-strand break occurs in the ALK, RET, ROS1 or NTRK1 tyrosine kinase. We found that translocations form spontaneously with several partners in the genome, generate functional fusion proteins and induce resistance to EGFR inhibitors. Several of these proteins reproduce precisely the fusions found in NSCLC patients either as original driver events or secondary to development of resistance to targeted therapy. Therefore, F-HTGTS is an approach that allows rapid and comprehensive mapping of tyrosine kinase fusions in the genome from common oncogenic kinases and provide insights on their mechanisms of formation.
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| Overall design |
We applied a genome-wide translocation technique we previously developed (High-Throughput Genomic Translocation Sequencing approach, HTGTS) to identify translocation partners from DNA double strand breaks (DSBs) introduced into the ALK intron 19 locus in PC-9 cell before and after treatment with EGFR inhibitors, osimertinib.
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| Contributor(s) |
Cheong T, Wang Q, Chiarle R |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Feb 20, 2021 |
| Last update date |
Apr 30, 2024 |
| Contact name |
Roberto Chiarle |
| E-mail(s) |
Roberto.Chiarle@childrens.harvard.edu
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| Organization name |
Children’s Hospital Boston and Harvard Medical School
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| Department |
Department of Pathology
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| Lab |
Roberto Chiarle
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| Street address |
300 Longwood Avenue
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| City |
Boston |
| State/province |
Massachusetts |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA703396 |
| SRA |
SRP307251 |
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