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Article

Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model

1
Division of Carcinogenesis, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
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Division of Pathology, The Cancer Institute, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
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Department of Pathology, Toranomon Hospital, Tokyo 105-8470, Japan
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Division of Orthopedic Oncology, The Cancer Institute Hospital, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
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Department of Orthopedic Surgery (Ohashi), School of Medicine, Toho University, Tokyo 143-8540, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(9), 2345; https://doi.org/10.3390/cancers12092345
Received: 2 July 2020 / Revised: 14 August 2020 / Accepted: 17 August 2020 / Published: 19 August 2020
(This article belongs to the Section Molecular Cancer Biology)
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. View Full-Text
Keywords: fusion gene; bone and soft tissue sarcomas; target RNA sequencing; mouse model; NTRK; inhibitor fusion gene; bone and soft tissue sarcomas; target RNA sequencing; mouse model; NTRK; inhibitor
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MDPI and ACS Style

Teramura, Y.; Tanaka, M.; Yamazaki, Y.; Yamashita, K.; Takazawa, Y.; Ae, K.; Matsumoto, S.; Nakayama, T.; Kaneko, T.; Musha, Y.; Nakamura, T. Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model. Cancers 2020, 12, 2345. https://doi.org/10.3390/cancers12092345

AMA Style

Teramura Y, Tanaka M, Yamazaki Y, Yamashita K, Takazawa Y, Ae K, Matsumoto S, Nakayama T, Kaneko T, Musha Y, Nakamura T. Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model. Cancers. 2020; 12(9):2345. https://doi.org/10.3390/cancers12092345

Chicago/Turabian Style

Teramura, Yasuyo, Miwa Tanaka, Yukari Yamazaki, Kyoko Yamashita, Yutaka Takazawa, Keisuke Ae, Seiichi Matsumoto, Takayuki Nakayama, Takao Kaneko, Yoshiro Musha, and Takuro Nakamura. 2020. "Identification of Novel Fusion Genes in Bone and Soft Tissue Sarcoma and Their Implication in the Generation of a Mouse Model" Cancers 12, no. 9: 2345. https://doi.org/10.3390/cancers12092345

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