Analysis of mutations in primary and metastatic synovial sarcoma
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Zhuo Xing1,*, Lei Wei2,*, Xiaoling Jiang1,*, Jeffrey Conroy3,4, Sean Glenn3,4, Wiam Bshara5, Tao Yu1,6, Annie Pao1, Shinya Tanaka7, Akira Kawai8, Christopher Choi9, Jianmin Wang2, Song Liu2,#, Carl Morrison3,4,5,# and Y. Eugene Yu1,10,#
1The Children's Guild Foundation Down Syndrome Research Program, Genetics and Genomics Program, Department of Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo, NY, USA
2Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
3Center for Personalized Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
4OmniSeq Inc., Buffalo, NY, USA
5Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
6Department of Medical Genetics, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
7Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
8Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
9Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
10Genetics, Genomics and Bioinformatics Program, State University of New York at Buffalo, Buffalo, NY, USA
*First three authors should be regarded as joint first authors
#Last three authors contributed equally to this paper
Y. Eugene Yu, email: email@example.com
Keywords: synovial sarcoma; SS18-SSX; metastasis; whole exome sequencing; ADAM 17
Received: October 11, 2018 Accepted: November 16, 2018 Published: December 07, 2018
Synovial sarcoma is the most common pediatric non-rhabdomyosarcoma soft tissue sarcoma and accounts for about 8–10% of all soft tissue sarcoma in childhood and adolescence. The presence of a chromosomal translocation-associated SS18-SSX-fusion gene is causally linked to development of primary synovial sarcoma. Metastases occur in approximately 50–70% of synovial sarcoma cases with yet unknown mechanisms, which led to about 70–80% mortality rate in five years. To explore the possibilities to investigate metastatic mechanisms of synovial sarcoma, we carried out the first genome-wide search for potential genetic biomarkers and drivers associated with metastasis by comparative mutational profiling of 18 synovial sarcoma samples isolated from four patients carrying the primary tumors and another four patients carrying the metastatic tumors through whole exome sequencing. Selected from the candidates yielded from this effort, we examined the effect of the multiple missense mutations of ADAM17, which were identified solely in metastatic synovial sarcoma. The mutant alleles as well as the wild-type control were expressed in the mammalian cells harboring the SS18-SSX1 fusion gene. The ADAM17-P729H mutation was shown to enhance cell migration, a phenotype associated with metastasis. Therefore, like ADAM17-P729H, other mutations we identified solely in metastatic synovial sarcoma may also have the potential to serve as an entry point for unraveling the metastatic mechanisms of synovial sarcoma.
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