Abstract 17: Proteogenomic characterization of pancreatic ductal adenocarcinoma
Authors: Cao Liwei , Huang Chen , Zhou Daniel Cui , Bathe Oliver F. , Chan Daniel W. , Hruban Ralph H. , Ding Li , Zhang Bing , Zhang Hui ,   Clinical Proteomic Tumor Analysis Consortium Investigators
Published: July 2021

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive cancer with 5-year survival rate less than 10%. Although numerous efforts have been made to characterize the functional driver genes of PDAC, the impacts of genomic alterations on protein modifications and molecular mechanism of this cancer type are still not well defined. To this end, Investigators from The Clinical Proteomic Tumor Analysis Consortium (CPTAC) conducted the first comprehensive characterization of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues using whole genome sequencing, whole exome sequencing, methylation, RNA-seq, miRNA-seq, proteomics, phosphoproteomics, and glycoproteomics. To address the inherent low neoplastic cellularity of pancreatic cancer, multiple orthogonal strategies using molecular features and histology imaging were deployed to deconvolute the cellularity and identify 105 tumors with sufficient neoplastic purity for downstream analyses. Proteomics, phosphoproteomics, and glycoproteomics analyses by mass spectrometry identified and quantified 11,662 proteins, 51,469 phosphosites, and 34,024 glycopeptides, respectively. Genomic data revealed that 97% of the cancers harbored KRAS alterations in our cohort. In addition, we found that somatic mutations and copy number alterations could impact gene and protein expression, as well as protein modifications such as phosphorylation and glycosylation. Glycoproteomic analyses uncovered tumor-associated alterations in glycoprotein biosynthesis and glycoproteins as potential targets for diagnosis or therapeutic intervention. Over-expressed kinase substrates and their corresponding kinases were identified with integration of global proteomic and phosphoproteomic measurements, thus identifying potential therapeutic targets. The results of our molecular and cellular subtyping revealed a small group of immune-hot subtype tumors that could benefit from immunotherapy, as well as the underlying mechanisms associated with major groups of immune-cold subtypes, including endothelial cell remodeling, glycolysis, and cell junction dysregulation. Non-negative matrix factorization (NMF)-based proteogenomics subtyping revealed two clusters with strong prognostic relevance. Finally, we identified proteins and glycoproteins overexpressed in early stage pancreatic cancer that may serve as candidates for early detection. This comprehensive proteogenomic characterization of PDAC provides a valuable resource for uncovering the molecular mechanisms of this cancer and thus paves the way for discovery of novel early detection and therapeutic targets.
Citation Format: Liwei Cao, Chen Huang, Daniel Cui Zhou, Oliver F. Bathe, Daniel W. Chan, Ralph H. Hruban, Li Ding, Bing Zhang, Hui Zhang, Clinical Proteomic Tumor Analysis Consortium Investigators. Proteogenomic characterization of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 17.