Understanding cell lineage and tumorigenesis in Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) through super-enhancer analysis
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive type of ovarian cancer primarily occurring in girls and young women. SCCOHT is universally driven by the mutation-based inactivation and epigenetic silencing of the SMARCA4 and SMARCA2 ATPase subunits, respectively, in the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. In rhabdoid tumor (RT), another SWI/SNF-loss-driven malignancy, super-enhancers (SEs), large (~3-12.5 kilobases) clusters of regulatory enhancer regions marked by high levels of histone 3 lysine 27 acetylation (H3K27ac), retain SWI/SNF binding despite the loss of SWI/SNF binding at normal enhancers. Because of their preservation in reduced SWI/SNF conditions, role in defining normal cell lineage, and association with oncogenes across various cancers, SEs present as a potential analytical and translational target in SCCOHT, whose cell of origin is unknown. I identified and clustered SEs based on H3K27ac ChIP-Seq signal in two SCCOHT cell lines as well as five putative cell-of-origin types using standard bioinformatics tools. After distinguishing cell types that shared unique SEs with SCCOHT, such as neuroepithelial and neural progenitor cells, I pinpointed SE regions associated with known oncogenes. Specifically, I identified a region unique to neuronal, RT, and SCCOHT lines associated with the oncogene SALL4. The SALL4-associated SE region is diminished in an SCCOHT cell line with re-expressed SMARCA4, indicating the dependency of SALL4 on SMARCA4 ATPase inactivation in SCCOHT. The SEs shared between neuronal, SCCOHT, and RT cells may indicate a possible cell of origin for SCCOHT of the neuronal cell lineage, and the data obtained provide a starting point for experimentation to verify the role of specific SEs and their associated oncogenes in SCCOHT tumorigenesis.
