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A Mouse Model of Incompletely Resected Soft Tissue Sarcoma for Testing Neoadjuvant Therapies
Published on: July 28, 2020
Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a
Yasuyo Teramura1, Miwa Tanaka1, Yukari Yamazaki1
1Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
Abstract:
Fusion genes induced by chromosomal aberrations are common mutations causally associated with bone and soft tissue sarcomas (BSTS). These fusions are usually disease type-specific, and identification of the fusion genes greatly helps in making precise diagnoses and determining therapeutic directions. However, there are limitations in detecting unknown fusion genes or rare fusion variants when using standard fusion gene detection techniques, such as reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). In the present study, we have identified 19 novel fusion genes using target RNA sequencing (RNA-seq) in 55 cases of round or spindle cell sarcomas in which no fusion genes were detected by RT-PCR. Subsequent analysis using Sanger sequencing confirmed that seven out of 19 novel fusion genes would produce functional fusion proteins. Seven fusion genes detected in this study affect signal transduction and are ideal targets of small molecule inhibitors. YWHAE-NTRK3 expression in mouse embryonic mesenchymal cells (eMCs) induced spindle cell sarcoma, and the tumor was sensitive to the TRK inhibitor LOXO-101 both in vitro and in vivo. The combination of target RNA-seq and generation of an ex vivo mouse model expressing novel fusions provides important information both for sarcoma biology and the appropriate diagnosis of BSTS.
Insights
Researchers discovered 19 new fusion genes in bone and soft tissue sarcomas using RNA sequencing. One fusion, YWHAE-NTRK3, caused sarcoma in mice and responded to targeted therapy, offering new diagnostic and treatment insights.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Chromosomal aberrations leading to fusion genes are key drivers in bone and soft tissue sarcomas (BSTS).
- Current detection methods like RT-PCR and FISH have limitations in identifying novel or rare fusion genes.
- Accurate fusion gene identification is crucial for precise diagnosis and targeted therapy in sarcomas.
Purpose of the Study:
- To identify novel fusion genes in round or spindle cell sarcomas using advanced sequencing techniques.
- To validate the functionality and therapeutic potential of newly discovered fusion genes.
- To investigate the oncogenic role of a specific fusion gene (YWHAE-NTRK3) and its response to targeted inhibition.
Main Methods:
- Target RNA sequencing (RNA-seq) was employed on 55 sarcoma cases.
- Novel fusion genes were identified, and their functional protein production was confirmed via Sanger sequencing.
- An ex vivo mouse model was generated to study the YWHAE-NTRK3 fusion gene's effects.
Main Results:
- Nineteen novel fusion genes were identified in sarcomas previously negative for fusion genes by RT-PCR.
- Seven of these novel fusions were confirmed to produce functional proteins.
- The YWHAE-NTRK3 fusion induced spindle cell sarcoma in mice and demonstrated sensitivity to the TRK inhibitor LOXO-101.
- Seven identified fusion genes target signal transduction pathways, making them potential targets for small molecule inhibitors.
Conclusions:
- Target RNA-seq is effective for discovering novel fusion genes in BSTS, overcoming limitations of conventional methods.
- The identified fusion genes provide new avenues for precise diagnosis and therapeutic strategies in sarcomas.
- The YWHAE-NTRK3 fusion serves as a validated target for TRK inhibitors, highlighting potential personalized treatment approaches.
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