Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma

Chen, Y.; Su, Y.; Leo, I. R.; Siavelis, I.; Zeng, J.; Cao, X.; Tsagkozis, P.; Hesla, A. C.; Papakonstantinou, A.; Liu, X.; Huang, W.-K.; Ehnman, M.; Johansson, H.; Lin, Y.; Lehtiö, J.; Zhang, Y.; Larsson, O.; Haglund, F.

doi:10.1101/2022.05.09.490894

bioRxiv · 10.1101/2022.05.09.490894

Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma

Chen, Y.·Su, Y.·Leo, I. R.·Siavelis, I.·Zeng, J.·Cao, X.·Tsagkozis, P.·Hesla, A. C.·Papakonstantinou, A.·Liu, X.·Huang, W.-K.·Ehnman, M.·Johansson, H.·Lin, Y.·Lehtiö, J.·Zhang, Y.·Larsson, O.·Haglund, F.

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Abstract

Synovial sarcomas (SS) are malignant mesenchymal tumors characterized by the SS18-SSX fusion gene, which drives tumorigenesis by altering the composition of the BAF complex. Secondary genomic alterations that determine variations in tumor phenotype or clinical presentation are largely unknown. Herein, we present transcriptome, targeted DNA-sequencing, and proteomics analysis of 91 synovial sarcomas from 55 patients. We identified three SS clusters (SSCs) characterized by distinct histology, tumor microenvironments, genomic complexities, therapeutic effects, and clinical outcomes. Eight BAF complex components are differentially expressed among SSCs, and their role in mesenchymal-epithelial-transition is supported by single cell sequencing. The epithelial cells of biphasic tumors are more susceptible to developing copy number alterations, including amplification of PDCD1 and TMPRSS2. Our findings explain broad concepts in SS biology and imply that the BAF composition at the start of the tumorigenesis (i.e. the cellular linage) may determine the SS subtype, providing a rationale for individualized treatment strategies.

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Chen, Y., Su, Y., Leo, I. R., Siavelis, I., Zeng, J., Cao, X., Tsagkozis, P., Hesla, A. C., Papakonstantinou, A., Liu, X., Huang, W.-K., Ehnman, M., Johansson, H., Lin, Y., Lehtiö, J., Zhang, Y., Larsson, O., Haglund, F.. 2022-05-10. Integrative multi-omics analysis reveals molecular subtypes and tumor evolution of synovial sarcoma. https://doi.org/10.1101/2022.05.09.490894

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