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Qiu, Alvin

University of British Columbia

Synovial sarcoma is an aggressive soft tissue malignancy characterized by a pathognomonic chromosomal translocation leading to the production of SS18-SSX, a fusion oncoprotein which associates with BAF, a chromatin remodelling complex. BAF complexes exist in three main subtypes and recent research demonstrated that SS18-SSX drives the degradation of cBAF, leading to a relative increase in ncBAF and PBAF. I analyzed 31 cases of primary human synovial sarcoma using ChIP-seq for histone modifications, RNA-seq for transcriptomes, and whole genome bisulfite sequencing for DNA methylomes. In addition, I analyzed chromatin accessibility in 14 cases using scATAC-seq. Unsupervised hierarchical clustering of ChIP-seq density for active histone modifications (H3K27ac, H3K4me1, H3K4me3) reveals two major synovial sarcoma epigenetic subgroups: “Group 1” and “Group 2”. Enhancers from Group 1 tumors show lower levels of cBAF binding compared to enhancers from Group 2 tumors. Group 1 enhancers also show greater overlap with binding sites of oncogenic BAF complexes (from cell lines containing SS18-SSX) compared to non-oncogenic BAF complexes (from cell lines with SS18-SSX knockdown). Therefore, the differences in these subgroups could be driven by differences in SS18-SSX activity. This led to my hypothesis that synovial sarcomas can be subgrouped based on epigenomic state, and this relates to disease severity. In support, I demonstrate that Group 1 tumors are higher grade sarcomas and that treating synovial sarcoma cells with a histone deacetylase inhibitor or knockdown of SS18-SSX both cause proliferative arrest and increase the expression of Group 2 enhancer associated genes. scATAC-seq analyses reveal a rare cluster of cells (6%) shared among all tumors. These cells express SS18-SSX yet differ from all other malignant cells in their expression of synovial sarcoma signature genes, as predicted by open chromatin. The chromatin state of these cells is more correlated with the lower grade subgroup (Group 2) compared to higher grade subgroup (Group 1). These cells may therefore represent an intermediate/early malignant cell state. Overall, my analysis suggests that human synovial sarcomas can be classified by epigenomic state, which may reflect the activity of SS18-SSX. My findings are relevant for guiding emerging therapeutic strategies that target BAF complex imbalances.

Text

2024-06-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/81726

Interdisciplinary Oncology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/