Introduction Ovarian carcinomas are divided into five major histologies, each having distinguishable clinical and molecular characteristics. We sought out to identify regulatory elements and resulting expression signatures across tumor-epithelium and stromal compartments of the three most common ovarian carcinoma histotypes (high-grade serous = HGSOC, endometrioid = ENOC, clear cell ovarian carcinoma = CCOC) by measuring transcription and methylation.      
Method Laser-capture microdissection was used to separate cell compartments, and whole genome bisulfite and transcriptome sequencing was applied to CCOC (n=20), HGSOC (n=22), and ENOC (n=33). Immunohistochemistry was used to determine and confirm state of common molecular markers (e.g. WT1, p53, HNF1B, ER, PR).         
Results Transcriptome data confirmed previous findings including HFN1B overexpressed in CCOC, and high ESR1 levels in ENOC compared with CCOC epithelium. Differential gene expression analysis of epithelial compartments showed high levels of CLCN2 in ENOC and high expression of MYH2/14 was associated with endometriosis-associated types relative to HGSOC. Overall, stromal compartments showed less variability and heterogeneity, in both methylome and transcriptome analysis. Across histotypes, multiple highly expressed stromal genes showed promising interaction scores with approved drugs.         
Conclusion The tumor epithelial compartments of HGSOC, ENOC, and CCOC showed unique regulatory signatures, consistent with previous studies. The lack of stromal heterogeneity suggests that the tumor-associated-fibroblast component in particular may play an analogous role in tumor progression independent of histotype and points towards the underutilized power of compartment-specific integrative analysis. The uniformity in gene expression may be exploited with pan-ovarian carcinoma treatment strategies and our preliminary analysis suggest drug repurposing investigations are warranted in this context.