A Proteogenomic View of Synchronous Endometrioid Endometrial and Ovarian Cancer

Abstract Purpose: Increasing genomics-based evidence suggests that synchronous endometrial and ovarian cancer (SEOC) represents clonally related primary and metastatic tumors. A systematic analysis of the global protein landscape of SEOCs, heretofore lacking, could reveal functional and disease-specific consequences of known genetic alterations, the directionality of metastasis, and accurate histological markers to distinguish SEOCs from single-site tumors. Experimental Design: We performed a systematic proteogenomic analysis of 29 patients diagnosed with SEOC at three international gynecologic oncology treatment centers (Chicago, Vancouver, Tübingen). For direct comparison to single-site tumors, we included 9 patients with single-site endometrioid ovarian and 26 patients with single-site endometrial endometrioid cancer. For all 64 patients, we performed sequencing of a 275-gene cancer panel combined with compartment-resolved mass spectrometry (MS) based proteomics of consecutive tissue sections to compare global (6,000+ proteins), tumor, and stromal proteomes. Results: DNA-based panel sequencing confirmed that most SEOCs are clonally related. Global proteome profiling uncovered pronounced differences between SEOCs and single tumors and underscored the importance of the stromal proteome in defining and identifying SEOCs. We identified molecularly unique SEOC stromal proteomes, which were globally more related to single endometrial cancers. We finally derived a proteomic predictor distinguishing SEOCs from single-site ovarian and uterine tumors. Conclusions: The integrated proteogenomic data show that SEOCs are distinguishable from endometrial endometrioid or endometrioid ovarian cancers. Based on their proteogenomic similarity to endometrial endometrioid cancers, we conclude that most synchronous endometrial and ovarian cancers represent primary endometrial endometrioid cancers that have metastasized to the ovary.