Proteogenomic characterization of pancreatic ductal adenocarcinoma.

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From: Cell(Vol. 184, Issue 19)
Publisher: Elsevier B.V.
Document Type: Report
Length: 952 words

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Keywords pancreatic ductal adenocarcinoma; proteogenomics; KRAS; neoplastic cellularity; glycoproteins; kinase inhibitors; immune-cold tumors; endothelial cell; tumor subtyping; CPTAC Highlights * Proteogenomic characterization reveals the functional impact of genomic alterations * Phosphoproteomics uncovers putative therapeutic targets downstream of KRAS * Multiomics links endothelial cell remodeling and glycolysis to immune exclusion * Proteomics and glycoproteomics reveal candidates for early detection or intervention Summary Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets. Author Affiliation: (1) Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA (2) Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA (3) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA (4) Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA (5) McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA (6) Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA (7) Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA (8) The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA (9) Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA (10) Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada (11) Sema4, a Mount Sinai venture, Stamford, CT 06902, USA (12) Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA (13) Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA (14) Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada (15) Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA (16) Van Andel Research Institute, Grand Rapids, MI 49503, USA (17) Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA (18) Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA (19) Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA (20) Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA (21) Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada (22) The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21231, USA * Corresponding author Article History: Received 8 October 2020; Revised 19 March 2021; Accepted 18 August 2021 (miscellaneous) Published: September 16, 2021 (footnote)23 These authors contributed equally (footnote)24 These authors contributed equally (footnote)25 These authors contributed equally (footnote)26 Lead contact Byline: Liwei Cao (1,23), Chen Huang (2,3,23), Daniel Cui Zhou (4,5,23), Yingwei Hu (1,24), T. Mamie Lih (1,24), Sara R. Savage (2,3,24), Karsten Krug (6,24), David J. Clark (1,24), Michael Schnaubelt (1), Lijun Chen (1), Felipe da Veiga Leprevost (7), Rodrigo Vargas Eguez (1), Weiming Yang (1), Jianbo Pan (1), Bo Wen (2,3), Yongchao Dou (2,3), Wen Jiang (2,3), Yuxing Liao (2,3), Zhiao Shi (2,3), Nadezhda V. Terekhanova (4,5), Song Cao (4,5), Rita Jui-Hsien Lu (4,5), Yize Li (4,5), Ruiyang Liu (4,5), Houxiang Zhu (4,5), Peter Ronning (4,5), Yige Wu (4,5), Matthew A. Wyczalkowski (4,5), Hariharan Easwaran (8), Ludmila Danilova (9), Arvind Singh Mer (10), Seungyeul Yoo (11), Joshua M. Wang (12,13), Wenke Liu (12,13), Benjamin Haibe-Kains (10,14), Mathangi Thiagarajan (15), Scott D. Jewell (16), Galen Hostetter (16), Chelsea J. Newton (16), Qing Kay Li (1), Michael H. Roehrl (17,18), David Fenyö (12,13), Pei Wang (11), Alexey I. Nesvizhskii (7), D.R. Mani (6), Gilbert S. Omenn (19), Emily S. Boja (20), Mehdi Mesri (20), Ana I. Robles (20), Henry Rodriguez (20), Oliver F. Bathe (21,25), Daniel W. Chan (1,8,25), Ralph H. Hruban (1,8,22,25), Li Ding [lding@wustl.edu] (4,5,25,*), Bing Zhang [bing.zhang@bcm.edu] (2,3,25,**), Hui Zhang [huizhang@jhu.edu] (1,8,25,26,***), Mitual Amin, Eunkyung An, Christina Ayad, Thomas Bauer, Chet Birger, Michael J. Birrer, Simina M. Boca, William Bocik, Melissa Borucki, Shuang Cai, Steven A. Carr, Sandra Cerda, Huan Chen, Steven Chen, David Chesla, Arul M. Chinnaiyan, Antonio Colaprico, Sandra Cottingham, Magdalena Derejska, Saravana M. Dhanasekaran, Marcin J. Domagalski, Brian J. Druker, Elizabeth Duffy, Maureen A. Dyer, Nathan J. Edwards, Matthew J. Ellis, Jennifer Eschbacher, Alicia Francis, Jesse Francis, Stacey Gabriel, Nikolay Gabrovski, Johanna Gardner, Gad Getz, Michael A. Gillette, Charles A. Goldthwaite Jr., Pamela Grady, Shuai Guo, Pushpa Hariharan, Tara Hiltke, Barbara Hindenach, Katherine A. Hoadley, Jasmine Huang, Corbin D. Jones, Karen A. Ketchum, Christopher R. Kinsinger, Jennifer M. Koziak, Katarzyna Kusnierz, Tao Liu, Jiang Long, David Mallery, Sailaja Mareedu, Ronald Matteotti, Nicollette Maunganidze, Peter B. McGarvey, Parham Minoo, Oxana V. Paklina, Amanda G. Paulovich, Samuel H. Payne, Olga Potapova, Barbara Pruetz, Liqun Qi, Nancy Roche, Karin D. Rodland, Daniel C. Rohrer, Eric E. Schadt, Alexey V. Shabunin, Troy Shelton, Yvonne Shutack, Shilpi Singh, Michael Smith, Richard D. Smith, Lori J. Sokoll, James Suh, Ratna R. Thangudu, Shirley X. Tsang, Ki Sung Um, Dana R. Valley, Negin Vatanian, Wenyi Wang, George D. Wilson, Maciej Wiznerowicz, Zhen Zhang, Grace Zhao

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Gale Document Number: GALE|A675779385