Abstract 4318: Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis

Abstract

Abstract Over 94% of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), a rare and aggressive form of ovarian cancer, have mutations and concomitant protein loss in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. SCCOHT tumors rarely have secondary mutations, making them an excellent model for understanding the role BRG1 and SWI/SNF complexes play in tumor suppression. We hypothesize that BRG1 loss drives SCCOHT tumorigenesis by altering chromatin accessibility and gene expression. We have previously shown that BRG1 re-expression in SCCOHT cell lines suppresses cell growth and induces an elongated, neuronal-like morphology. To identify the top genes and transcription factors driving SCCOHT tumorigenesis, we performed ATAC-seq and RNA-seq in a SCCOHT cell line +/- BRG1 re-expression. BRG1 re-expression increased overall chromatin accessibly, shown by an increase in the number of ATAC-seq peaks. ATAC peaks gained following BRG1 re-expression were enriched in transcription factor binding motifs from FOS/JUN/AP-1, TEAD, and SOX family members. RNA-seq analysis demonstrated that BRG1 re-expression upregulated more genes than those downregulated, consistent with the increase in ATAC-seq peaks. Preliminary pathway analysis identified gene enrichments in epithelial-mesenchymal transition pathway and extracellular matrix remodeling following BRG1 re-expression, consistent with the observed morphology change. Cell types enrichment analysis (xCell) identified a shift from a mesenchymal stem cell-like gene signature in the control SCCOHT cells to an epithelial cell-like gene signature following BRG1 re-expression, further suggesting a possible mesenchymal-epithelial transition in SCCOHT cells after BRG1 re-expression. Future studies include integration of the ATAC/RNA-seq data to further identify correlations between gene expression changes and enriched transcription factor binding motifs, integrative ChIP-seq analysis for BRG1 following re-expression, and proteomic analyses. These studies will uncover the key genes, proteins, and transcription factors affected by BRG1 loss in other adult cancers, provide insight into BRG1's role in SCCOHT tumorigenesis, and potentially yield novel therapeutic targets. Citation Format: Krystal A. Orlando, Jesse R. Raab, Jessica D. Lang, William P. Hendricks, Yemin Wang, David G. Huntsman, Jeffrey M. Trent, Joel S. Parker, Bernard E. Weissman. Identifying drivers of SMARCA4/BRG1-deficient SCCOHT tumorigenesis by integrative multi-omic analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4318.