Abstract SY44-03: Proteogenomic and phosphoproteomic analysis of ovarian cancer

Abstract

Abstract A comprehensive molecular level view of cancer is desirable for understanding the underlying causes of disease, for predicting prognosis, and ultimately guiding treatment. The Cancer Genome Atlas (TCGA) conducted an extensive genomic and transcriptomic characterization of ovarian high-grade serous carcinoma (HGSC) with the objective of informing prognosis and the development of targeted therapies for this highly lethal gynecologic malignancy1. However, proteins are likely closer to biological and disease phenotypes, often not well correlated with their transcripts, and their characterization is expected to provide insights not evident from genomic studies. Therefore, to obtain a more comprehensive assessment of the complex HGSC phenotype, the Clinical Proteomic Tumor Analysis Consortium (CPTAC) conducted an extensive proteomic and phosphoproteomic characterization of the HGSC tumors previously characterized by TCGA, providing quantitative measurements for 10,030 proteins across 174 tumors, and 25,598 phosphosites from 6,769 phosphoproteins. Novel insights into ovarian cancer biology arising from these proteogenomic studies include: 1) a substantial trans-regulation of protein abundances by copy number alterations (CNAs), which when analyzed at a pathway level converged on the cancer-associated processes of proliferation, cell motility/invasion, and immune regulation; 2) identification of five proteomic subtypes in the TCGA cohort, with two subtypes showing robust concordance with the mesenchymal and proliferative subtypes, and tumors from transcript assigned differentiated and immunoreactive subtypes not robustly segregating into distinct clusters, demonstrating their proteomic heterogeneity; 3) identification of specific post-translational modifications associated with homologous repair deficiency; and 4) phosphoproteomic data revealing a consistent novel set of activated pathways associated with patient survival, including up-regulation of VEGFR signaling in patients with poor outcomes, and suggesting a strategy for selecting anti-angiogenesis therapies. This study will inform future use of protein markers to stratify patients who may benefit from anti-angiogenesis or PARP inhibitor therapy, predicting development of platinum resistant disease, identifying immunoregulatory networks that can be exploited for cancer immunotherapy, and determining the clinical phenotypes based upon proteomic ovarian cancer subtypes. Citation Format: Karin D. Rodland. Proteogenomic and phosphoproteomic analysis of ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr SY44-03. doi:10.1158/1538-7445.AM2015-SY44-03