Abstract 6580: Proteogenomic characterization of endometrial carcinoma

Abstract

Abstract Endometrial cancer (EC) is the sixth most common cancer in women globally and is one of the few cancers for which mortality is increasing; to address the need to develop new methods for the diagnosis and treatment of this disease, we performed a comprehensive proteogenomic characterization of 95 endometrial carcinomas. We prospectively collected 83 endometrioid and 12 serous tumors, along with 49 normal tissue samples, for multi-omic characterization. Each sample underwent whole exome sequencing, whole genome sequencing, total RNA and miRNA sequencing, and DNA methylation array analyses. In addition, we evaluated all samples for protein, phosphorylation, and acetylation levels using an integrated, isobaric tandem mass tag labeling–based quantitative proteomics workflow. This dataset, publicly available through the Genomic Data Commons, CPTAC data portal, and other sources, provides a valuable resource for researchers and clinicians. Our analyses of these tumors revealed, among other things, a potential role for circRNAs in the epithelial-mesenchymal transition and new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. We found possible new consequences of perturbations to the Wnt/β-catenin pathway, particularly CTNNB1 hotspot mutations; moreover, from the genome-wide acetylation survey, we found potential regulatory mechanisms linking Wnt signaling and histone acetylation. Phosphorylation data analysis suggests an elevated DNA damage response in serous tumors, which we hypothesize may be targetable by certain FDA-approved drugs. We found that TP53 hotspot mutations play unique trans-acting roles as compared to the same mutations in colon and ovarian cancers. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions; of particular translational interest, we identified a subset of patients who, despite having high amounts of microsatellite instability, exhibit biomarkers which suggest that immunotherapy would be an ineffective treatment for their disease. By integrating global measurements of protein abundance, phosphorylation, and acetylation with next-generation genomics and transcriptomics, we have provided novel insights into biological processes underlying the development of endometrial cancers and generated strong hypotheses for new approaches to personalized treatment of individuals with endometrial cancer. Citation Format: Emily A. Kawaler, Yongchao Dou, Daniel Cui Zhou, Marina A. Gritsenko, Karin D. Rodland, Li Ding, Bing Zhang, Tao Liu, David Fenyö, Clinical Proteomic Tumor Analysis Consortium. Proteogenomic characterization of endometrial carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6580.